Clinical trial NCT02634580
Conditions: Hypercholesterolemia
Keywords: Japanese High cholesterol Treatment of high cholesterol Lowering cholesterol Lowering high cholesterol Hypercholesterolemia Statin intolerant
Sponsor: Amgen
Start date: 2016-02-27; Completion date: 2018-05-26
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study was to evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab compared with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic adults unable to tolerate an effective dose of a statin.

Detailed description:
After screening participants who met all inclusion/exclusion criteria were randomized with an allocation ratio of 2:2:1:1 into 4 groups: evolocumab (AMG 145) 420 mg administered by subcutaneous injection monthly and placebo pill daily; evolocumab 140 mg administered by subcutaneous injection every two weeks and placebo pill by mouth daily; placebo 420 mg administered by subcutaneous injection monthly and ezetimibe 10 mg pill daily; placebo 140 mg administered subcutaneous injection every two weeks and ezetimibe 10 mg pill daily. Randomization was stratified by screening LDL-C level and baseline statin use. Participants on low or atypical statin dose therapy must have been on a stable dose for at least 4 weeks prior to screening and throughout the blinded portion of the study; the dose could not be adjusted during screening and for the duration of the study. After Week 12, ezetimibe was discontinued and participants moved to an open-label dose of evolocumab administered by subcutaneous injection either every two weeks or monthly and their standard of care.

Arms: arm 1: Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48. arm 2: Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48. arm 3: Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48. arm 4: Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48.
Interventions: intervention 1: Evolocumab intervention 2: Ezetimibe intervention 3: Placebo to Evolocumab intervention 4: Placebo Ezetimibe
Intervention descriptions: intervention 1: Administered by subcutaneous injection intervention 2: Tablet for oral administration intervention 3: Administered by subcutaneous injection intervention 4: Tablet for oral administration

Protocol documents:
Prot_000.pdf: 
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NCT Number: 2634580 
This NCT number has been applied to the document  
for purposes of posting on clinicaltrials.gov


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 2 of 87 
Investigator’s Agreement 
I have read the attached protocol entitled A Double-blind, Randomized, Multicenter 
Study to Evaluate the Safety and Efficacy of Evolocumab, Compared With Ezetimibe, in 
Hypercholesterolemic Japanese Subjects Unable to Tolerate an Effective Dose of a 
HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects (GAUSS-4:  Goal 
Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects), dated 
21 March 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) 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) 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 3 of 87 
Protocol Synopsis 
Title:  A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of 
Evolocumab, Compared With Ezetimibe, in Hypercholesterolemic Japanese Subjects Unable to 
Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side 
Effects (GAUSS-4:  Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant 
Subjects) 
Study Phase:  Phase 3 
Indication:  Hypercholesterolemia 
Primary Objective:  To evaluate the effect of 12 weeks of subcutaneous evolocumab compared 
with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in 
hypercholesterolemic subjects unable to tolerate an effective dose of a statin. 
Secondary Objective(s):  
• 
To evaluate the safety and tolerability of subcutaneous (SC) evolocumab, compared 
with ezetimibe, in hypercholesterolemic subjects unable to tolerate an effective dose of a 
statin 
• 
To assess the effects of 12 weeks of evolocumab, compared with ezetimibe, on change 
from baseline in LDL-C, and percent change from baseline in non high density lipoprotein 
cholesterol (non HDL-C), total cholesterol (TC), apolipoprotein B (ApoB), total 
cholesterol/HDL-C ratio, ApoB/Apolipoprotein A1 (ApoA1) ratio, lipoprotein(a) [Lp(a)], 
triglycerides, very low-density lipoprotein cholesterol (VLDL-C), and HDL-C in 
hypercholesterolemic subjects unable to tolerate an effective dose of a statin 
• 
To assess the effects of 12 weeks SC evolocumab, compared with ezetimibe, on percent 
of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in hypercholesterolemic subjects 
unable to tolerate an effective dose of a statin 
Hypotheses:  The primary hypothesis is that evolocumab (AMG 145) SC will be well tolerated 
and will result in greater reduction of LDL-C than ezetimibe, defined by the mean percent change 
from baseline at week 10 and 12 and percent change from baseline at week 12. 
Co-Primary Endpoints:  
• 
Mean percent change from baseline in LDL-C at weeks 10 and 12 
• 
Percent change from baseline in LDL-C at week 12 
Secondary Endpoint(s): 
• 
Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for: 
Tier 1 
• 
Change from  baseline in LDL-C 
• 
LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L]) 
• 
Percent change from  baseline in total cholesterol 
• 
Percent change from  baseline in non-HDL-C  
• 
Percent change from  baseline in ApoB 
• 
Percent change from  baseline in the total cholesterol/HDL-C ratio 
• 
Percent change from  baseline in ApoB/ApoA1 ratio 
Tier 2 
• 
Percent change from  baseline in Lp(a) 
• 
Percent change from  baseline in triglycerides  
• 
Percent change from  baseline in HDL-C 
• 
Percent change from  baseline in VLDL-C 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 4 of 87 
Study Design:  This is a phase 3, multicenter, double-blind, randomized, ezetimibe controlled, 
parallel group study for evolocumab in hypercholesterolemic Japanese subjects unable to tolerate 
an effective dose of a statin.  Subjects who meet all inclusion/exclusion criteria will be randomized 
with an allocation ratio of 2:2:1:1 into 4 groups: evolocumab 420 mg SC QM + placebo PO QD, 
evolocumab 140 mg SC every 2 weeks (Q2W) + placebo PO QD, placebo QM SC + ezetimibe 
10 mg PO QD, placebo SC Q2W + ezetimibe 10 mg PO QD. Randomization will be stratified by 
screening LDL-C level and baseline statin use.  Randomization should occur within 5 – 10 days of 
the screening LDL-C evaluation used to determine eligibility.  Subjects on low or atypical statin 
therapy must be on a stable dose for at least 4 weeks prior to screening and throughout 
the blinded portion of the study; the dose cannot be adjusted during screening and for the 
duration of the study. 
To ensure tolerance of SC injections, patients will receive a 1-time placebo injection by AI/Pen 
prior to randomization. 
For blinding purposes, every subject will receive investigational product (IP) SC and PO.  
Subjects will be provided with evolocumab or placebo through the use of a prefilled 
autoinjector/pen (AI/Pen) or Pe rsonal Injector (also known as the automated mini-doser [AMD]). 
Depending on availability either a single Personal Injector will be provided for monthly dosing 
(QM) or QM evolocumab may be provided by the use of 3 autoinjectors. Evolocumab and 
corresponding placebo will be administered at the study site or at an appropriate non-clinic setting 
per protocol Table 1 (Schedule of Assessment). PO placebo will be available to match PO 
ezetimibe through over-encapsulation. The SC IP dose frequencies of Q2W and QM will not be 
blinded.  Evolocumab SC, ezetimibe PO, and placebo SC and PO will be blinded.  Central 
laboratory results of the lipid panel, ApoA1, ApoB, lipoprotein(a), and high sensitivity C-reactive 
protein (hsCRP) will be blinded during double-blind treatment.  Investigators will be provided lipid 
results starting at week 24 until the end of study for each subject.  All lipid results from 
posttreatment to week 24 will remain blinded until the unblinding of the clinical database. 
Subjects will self-administer IP in the non-clinic setting and return to the clinical site at W24, W36, 
W48 and W52 for subsequent visits. There will be an end of study phone call at W54 
(Q2W subjects only) for any potential adverse events/serious adverse events/adverse device 
effects. 
The study includes collection of biomarker samples, where approved by the institutional review 
board (IEC/IRB).  Administration of non-Amgen IP: PO IP (ezetimibe or placebo) will end with the 
week 12 visit for all subjects. Following the week 12 visit subjects should be treated to standard of 
care in addition to receiving Amgen IP: open label evolocumab. 
Subjects will be encouraged to complete all planned visits regardless of their adherence to 
investigational product (IP) administration.  The study includes a formal review of the 
accumulating blinded data by an independent Data Monitoring Committee (DMC).  
Sample Size:  Approximately 60 subjects (approximately 40 evolocumab subjects) will be 
randomized.  A subject will be considered enrolled upon randomization. 
Investigational Product(s) Dosage, Administration, Protocol-required Therapies, and 
Standard of Care: 
Amgen Investigational Product Dosage and Administration 
Evolocumab will be administered using a spring-based prefilled  autoinjector/pen (prefilled 
AI/Pen) or 3.5 mL Personal Injector. 
Evolocumab will be administered at 1 of 2 regimens: 
Evolocumab 140 mg SC Q2W (1 prefilled AI/Pen injection) or 
Evolocumab 420 mg SC QM (3 prefilled AI/Pen injections or 1 Personal Injector injection) 
Non Amgen Investigational Product Dosage and Administration:  Ezetimibe 10 mg 
(and placebo) will be provided by Amgen (or designee) and will be taken by the subject PO QD.  
Placebo will be matching ezetimibe by over-encapsulation. 
Amgen will not provide Standard of Care (SOC) medication for the open label period. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 5 of 87 
Summary of Subject Eligibility Criteria:  Males and females, ≥ 20 to ≤ 80 years of age, 
Japanese by self-identification, are eligible for this study.  Subject must have tried and failed at 
least 2 statins with failure to at least 1 of the statins at an average daily dose at or below the 
following doses due to intolerable myopathy, ie, myalgia (muscle pain, ache, or weakness without 
CK elevation), myositis (muscle symptoms with increased CK levels), or rhabdomyolysis (muscle 
symptoms with marked CK elevation). For subjects that developed rhabdomyolysis, defined as 
CK > 10 x ULN, failure of only 1 statin at any dose is acceptable. 
• 
Atorvastatin 
10 mg 
• 
Fluvastatin 
20 mg 
• 
Pravastatin 
10 mg 
• 
Rosuvastatin 
2.5 mg 
• 
Simvastatin 
5 mg 
• 
Pitavastatin 
1 mg 
• 
For unlisted statins, the average daily dose should not exceed the lowest available 
recommended starting dose approved by the Japanese Ministry of Health, Labour and 
Welfare. 
Symptoms must have resolved or improved when statin was discontinued or the dose was 
reduced.  Depending on a subject’s management category per 2012 JAS guideline 
(see Appendix D) subjects must meet criteria provided.  Fasting triglycerides must be 
≤ 400 mg/dL (4.5 mmol/L) as determined by the central laboratory analysis at screening. 
Major exclusion criteria include, but are not limited to moderate to severe heart failure, 
uncontrolled cardiac arrhythmia, symptomatic coronary artery disease within the last 3 months, 
recently diagnosed or poorly controlled diabetes, hypertension or hyper/hypothyroidism, known 
active infection or major hematologic, renal, hepatic, metabolic, gastrointestinal or endocrine 
dysfunction, systemic steroid use, pregnancy or lactation, previous exposure to evolocumab or 
other PCSK9 inhibitor. 
Statistical Considerations:   
General Considerations 
When all the randomized subjects in the study have either completed the scheduled visits up to 
and including Week 24 or have early terminated from the study, a primary analysis will be 
performed.  Efficacy and safety of 12 weeks of evolocumab compared with ezetimibe will be 
evaluated on the full analysis set (FAS) that includes all randomized subjects who received at 
least 1 dose of IP in the double blind treatment period.  In addition, the 12 weeks of data from 
the open-label extension (weeks 12 to 24) will also be summarized.  The treatment effect of 
evolocumab compared to ezetimibe will be evaluated for all efficacy endpoints through the 
Week 12 visit.  In addition, descriptive analyses from the open-label extension 
(weeks 12 to 24) will be performed on the open label extension analysis set (OLEAS).  
Methods of adjusting for multiplicity are provided in Section 10. 
The final analysis will be conducted to evaluate the long-term efficacy and safety of evolocumab 
when all enrolled subjects have either completed the scheduled visits or have early terminated 
from the study. 
Analyses of Co-primary Endpoints 
To assess the co-primary endpoints of the mean percent change in LDL-C from baseline at 
weeks 10 and 12 and the percent change from baseline at week 12, a repeated measures linear 
effects model will be used to compare the efficacy of evolocumab (pooled Q2W and QM) with the 
pooled ezetimibe. Missing values will not be imputed when the repeated measures linear model is 
used.  
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 6 of 87 
Analyses of Co-Secondary Efficacy Endpoints 
The statistical model for the co-secondary efficacy endpoints will be similar to the co-primary 
endpoints. However, the co-secondary efficacy endpoints of LDL-C response will be analyzed 
using the Cochran-Mantel Haenszel (CMH) test. 
Safety analyses 
Safety summaries will include the subject incidence of adverse events, summaries of laboratory 
parameters and anti-evolocumab antibodies. 
For a full description of statistical analysis methods, please refer to Section 10. 
 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version/Date: 
Version 5/20 March 2015 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 7 of 87 
Study 20140234 Treatment Schema 
Day 1
Week 54
Phone 
Call
Week 12
Screening
and
Placebo Injection
Randomization 2:1:2:1
Max ~28 Days
End of Study
Week 4
Week 10
Evolocumab QM 
+ 
Placebo PO
SC Placebo Q2W
+ 
Ezetimibe PO
Open Label Evolocumab QM
+
SOC
Week 36
Week 48
Week 24
Week 52
SC Placebo QM
+ 
Ezetimibe PO
Evolocumab Q2W 
+ 
Placebo PO
Open Label Evolocumab Q2W
+
SOC
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 8 of 87 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
AHA 
American Heart Association 
AI/Pen 
Autoinjector/pen 
ALP 
Alkaline phosphatase 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic-pyruvic transaminase) 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic 
transaminase) 
AUC 
Area under the curve 
BP 
Blood pressure 
CABG 
Coronary artery bypass graft 
CAS 
Completer analysis set 
CBC 
Complete blood count 
CETP 
Cholesterylester transfer protein 
CHD 
Coronary heart disease 
CK 
Creatine kinase 
CRP 
C-reactive protein 
CTCAE 
NCI Common Terminology Criteria for AEs 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DBP 
Diastolic blood pressure 
DILI 
Drug-induced liver injury 
DMC 
Data monitoring committee  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate; eGFR will be calculated by the 
central laboratory and provided to the investigator. 
End of study 
The end of the study is defined as the last day on which a 
randomized subject completes the study or the day the subjects 
terminates the study early. 
End of study for individual 
subject 
Defined as the last day that protocol-specified procedures are 
conducted for an individual subject or the day the subject withdraws 
from study early.     
End of treatment 
Defined as the day a subject receives the last treatment with 
investigational product before the subject completes the study or 
ends the treatment early. 
Enrollment 
A subject is considered enrolled upon randomization   
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 9 of 87 
Abbreviation or Term 
Definition/Explanation 
EOS 
End of study (for individual subject) 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCV 
Hepatitis C virus 
HDL-C 
High density lipoprotein cholesterol 
HepG2 cells 
Human hepatocellular carcinoma cell line 
HR 
Heart Rate 
hsCRP 
High sensitivity CRP 
IBG 
Independent Biostatistical Group 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC/IRB 
Independent Ethics Committee / Institutional Review Board 
IFU 
Instructions for use 
INR 
International normalized ratio 
IP 
Investigational product 
IPIM 
Investigational Product Instruction Manual 
IVRS/IWRS 
Interactive Voice Response System / Interactive Web Response 
System 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDLR 
LDL receptor 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantitation 
LOCF 
Last observation carried forward 
LOF 
Loss of function 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical dictionary for regulatory activities 
Muscle Symptoms 
Muscle pain, aches, weakness, cramps 
NASH 
Nonalcoholic steatohepatitis 
NOAEL 
No-observed-adverse-effect level 
OLE 
Open Label Extension 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 10 of 87 
Abbreviation or Term 
Definition/Explanation 
OLEAS 
Open Label Extension Analysis Set 
PBO 
Placebo 
PCI 
Percutaneous coronary intervention 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PKPD 
Pharmacokinetic / pharmacodynamics 
PO 
Oral administration 
Q2W 
Q2W is defined as every 2 weeks with a window of ± 3 days 
Q4W 
Every 4 weeks, (AMG 145 Background Section) 
QD 
Each day 
QM 
QM is defined as every 4 weeks with a window of ± 7 days 
QW 
Every week 
Randomized 
Assignment to treatment group based on computer-generated 
randomization schedules prepared by Amgen before the start of the 
study 
RAS 
Rechallenge Analysis Set 
RBC 
Red blood cells 
RR 
Respiratory rate 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SF-36 
Short Form (36) Health Survey 
Source Data 
Information from an original record or certified a 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 ID, 
Randomization ID, and Stratification Value. 
TBL 
Total bilirubin 
TIA 
Transient ischemic attack 
Tmax 
Time to maximum concentration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
VLDL-C 
Very low-density lipoprotein cholesterol 
WBC 
White blood cell 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 11 of 87 
TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study 20140234 Treatment Schema ................................................................................ 7 
Study Glossary .................................................................................................................. 8 
1. 
OBJECTIVES ......................................................................................................... 15 
1.1 
Primary ....................................................................................................... 15 
1.2 
Secondary .................................................................................................. 15 
2. 
BACKGROUND AND RATIONALE ........................................................................ 15 
2.1 
Disease ....................................................................................................... 15 
2.2 
Amgen Investigational Product Background ............................................... 18 
2.3 
Non-Amgen Medicinal Product Background ............................................... 19 
2.4 
Rationale .................................................................................................... 20 
2.5 
Clinical Hypotheses .................................................................................... 21 
3. 
EXPERIMENTAL PLAN ......................................................................................... 21 
3.1 
Study Design .............................................................................................. 21 
3.2 
Number of Sites .......................................................................................... 22 
3.3 
Number of Subjects .................................................................................... 22 
3.4 
Replacement of Subjects ............................................................................ 22 
3.5 
Estimated Study Duration ........................................................................... 22 
3.5.1 
Study Duration for Subjects ........................................................ 22 
3.5.2 
End of Study ............................................................................... 23 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 23 
4.1 
Inclusion and Exclusion Criteria ................................................................. 23 
4.1.1 
Inclusion Criteria ......................................................................... 23 
4.1.2 
Exclusion Criteria ........................................................................ 24 
5. 
SUBJECT ENROLLMENT ..................................................................................... 27 
5.1 
Randomization/Treatment Assignment ...................................................... 27 
5.2 
Site Personnel Access to Individual Treatment Assignments .................... 28 
6. 
TREATMENT PROCEDURES ............................................................................... 28 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 29 
6.2 
Investigational Product ............................................................................... 29 
6.2.1 
Amgen Investigational Product Evolocumab 
(AMG 145) .................................................................................. 29 
6.2.1.1 
Dosage, Administration, and Schedule .................... 30 
6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 30 
6.2.2 
Non-Amgen Investigational Product(s) ....................................... 30 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 12 of 87 
6.2.2.1 
Non-Amgen Investigational Product 
Ezetimibe ................................................................. 31 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 31 
6.3.1 
Criteria for Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 32 
6.3.2 
Criteria for Conditional Withholding of Amgen 
Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ................................. 33 
6.3.3 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity .............................................................. 33 
6.4 
Concomitant Therapy, Diet, and Exercise .................................................. 34 
6.5 
Medical Devices ......................................................................................... 34 
6.6 
Product Complaints, Including Device Complaints ..................................... 34 
6.7 
Excluded Treatments and/or Procedures During Study Period .................. 35 
7. 
STUDY PROCEDURES ......................................................................................... 36 
7.1 
Schedule of Assessments .......................................................................... 36 
7.2 
General Study Procedures ......................................................................... 39 
7.2.1 
Placebo Run-in ........................................................................... 41 
7.2.2 
Screening Enrollment and/or Randomization ............................. 41 
7.2.3 
Treatment ................................................................................... 42 
7.2.3.1 
Visit Day 1 (Randomization) .................................... 42 
7.2.3.2 
Visit/Week 2 ............................................................. 42 
7.2.3.3 
Week 4 ..................................................................... 43 
7.2.3.4 
Week 6 (Subjects on Q2W SC IP Only) ................... 43 
7.2.3.5 
Visit/Week 8 ............................................................. 43 
7.2.3.6 
Visit/Week 10 ........................................................... 44 
7.2.3.7 
Visit/Week 12 ........................................................... 44 
7.2.3.8 
Visit/Week 24 ........................................................... 45 
7.2.3.9 
Visit/Week 36 ........................................................... 45 
7.2.3.10 
Visit/Week 48 ........................................................... 45 
7.2.3.11 
Visit/Week 52 ........................................................... 45 
7.2.4 
Safety Follow-up / End of Study Phone Call/Week 54 
(± 3 days) ................................................................................... 46 
7.2.5 
Standardization of Study Procedures ......................................... 46 
7.2.5.1 
Measurement of Vital Signs ..................................... 46 
7.2.5.2 
Waist Circumference ................................................ 46 
7.2.5.3 
Lipid Measurements ................................................. 46 
7.3 
Antibody Testing Procedures ..................................................................... 47 
7.4 
Biomarker Development ............................................................................. 47 
7.5 
Sample Storage and Destruction ................................................................ 48 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 49 
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8.1 
Subjects’ Decision to Withdraw .................................................................. 49 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 50 
8.3 
Reasons for Removal From Treatment, or Study ....................................... 50 
8.3.1 
Reasons for Removal From Treatment ...................................... 50 
8.3.2 
Reasons for Removal From Study ............................................. 51 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 51 
9.1 
Adverse Events .......................................................................................... 51 
9.1.1 
Definition of Adverse Events ...................................................... 51 
9.1.2 
Definition of Serious Adverse Events ......................................... 52 
9.2 
Reporting of Adverse Events ...................................................................... 52 
9.2.1 
Reporting Procedures for Adverse Events That do not 
Meet Serious Criteria .................................................................. 52 
9.2.2 
Reporting Procedures for Serious Adverse Events .................... 54 
9.2.3 
Reporting Serious Adverse Events After the Protocol-
required Reporting Period .......................................................... 55 
9.3 
Pregnancy and Lactation Reporting ........................................................... 56 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 57 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 57 
10.1.1 
Study Endpoints ......................................................................... 57 
10.1.2 
Analysis Sets .............................................................................. 58 
10.1.3 
Covariates and Subgroups ......................................................... 59 
10.2 
Sample Size Considerations ...................................................................... 59 
10.3 
Access to Individual Subject Treatment Assignments by Amgen 
or Designees .............................................................................................. 60 
10.4 
Planned Analyses ....................................................................................... 60 
10.4.1 
Data Monitoring Committee (DMC) ............................................ 60 
10.4.2 
Primary Analysis ......................................................................... 60 
10.4.3 
Final Analysis ............................................................................. 60 
10.5 
Planned Methods of Analysis ..................................................................... 61 
10.5.1 
General Considerations .............................................................. 61 
10.5.2 
Primary Efficacy Endpoint .......................................................... 63 
10.5.3 
Secondary Efficacy Endpoints .................................................... 63 
10.5.4 
Tertiary Efficacy Endpoints Analyses ......................................... 64 
10.5.5 
Safety Endpoints ........................................................................ 64 
10.5.6 
Exploratory Endpoint Analyses ................................................... 64 
11. 
REGULATORY OBLIGATIONS ............................................................................. 65 
11.1 
Informed Consent ....................................................................................... 65 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 65 
11.3 
Subject Confidentiality ................................................................................ 66 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 67 
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12.1 
Protocol Amendments and Study Termination ........................................... 67 
12.2 
Study Documentation and Archive ............................................................. 67 
12.3 
Study Monitoring and Data Collection ........................................................ 68 
12.4 
Investigator Responsibilities for Data Collection ........................................ 69 
12.5 
Language.................................................................................................... 69 
12.6 
Publication Policy ....................................................................................... 69 
12.7 
Compensation ............................................................................................ 70 
13. 
REFERENCES ....................................................................................................... 71 
14. 
APPENDICES ........................................................................................................ 73 
List of Tables 
Table 1.  Schedule of Assessments ................................................................................ 37 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 74 
Appendix B.  Sample Electronic Serious Adverse Event Contingency 
Reporting Form ........................................................................................ 76 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 79 
Appendix D.  Japan Atherosclerosis Society (JAS) Guidelines for the 
Diagnosis and Prevention of Atherosclerotic Cardiovascular 
Diseases in Japan (2012) ........................................................................ 81 
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1. 
OBJECTIVES 
The main strategic objective of this study is to support the Japan LDL-C lowering 
submission for evolocumab in the setting of statin intolerance. The Pharmaceuticals 
Medical Devices Agency, Japan (PMDA) considers the Japanese (and East Asian) 
population to be distinct from the Caucasian population and requires additional data on 
the use of investigational drugs in their specific population. Further, PMDA has asked for 
a specific study in the statin intolerant Japanese population. This study will provide 
Amgen with additional data to support the use of evolocumab for treatment of Japanese 
hypercholesterolemic subjects that are unable to tolerate an effective dose of a 
HMG-CoA reductase inhibitor.  Protocol 20140234 is a phase 3 study to be conducted in 
Japan to address the unmet medical need of statin intolerance in this country 
Studies 20110116 (GAUSS-2) and 20130332 (GAUSS-3) are global phase 3 studies for 
statin intolerance that will be supplemented by this proposed protocol. 
1.1 
Primary 
To evaluate the effect of 12 weeks of subcutaneous evolocumab compared with 
ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol 
(LDL-C) in hypercholesterolemic subjects unable to tolerate an effective dose of a statin. 
1.2 
Secondary 
• 
To evaluate the safety and tolerability of subcutaneous (SC) evolocumab, 
compared with ezetimibe, in hypercholesterolemic subjects unable to tolerate an 
effective dose of a statin 
• 
To assess the effects of 12 weeks of evolocumab, compared with ezetimibe, on 
change from baseline in LDL-C, and percent change from baseline in non high 
density lipoprotein cholesterol (non HDL-C), total cholesterol (TC), apolipoprotein 
B (ApoB), total cholesterol/HDL-C ratio, ApoB/Apolipoprotein A1 (ApoA1) ratio, 
lipoprotein(a) [Lp(a)], triglycerides, very low-density lipoprotein cholesterol 
(VLDL-C), and HDL-C in hypercholesterolemic subjects unable to tolerate an 
effective dose of a statin 
• 
To assess the effects of 12 weeks SC evolocumab, compared with ezetimibe, on 
percent of subjects attaining LDL-C < 70 mg/dL (1.8 mmol/L) in 
hypercholesterolemic subjects unable to tolerate an effective dose of a statin 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
Some individuals are intolerant to statin therapy due to muscle-related side effects 
(Franc, Dejager et al, 2003, Bruckert, Hayem et al, 2005).  In the literature, terminology 
used to describe muscle-related side effects can be confusing, therefore in this 
document the terms described by Pasternak in the ACC/AHA/NHLBI Clinical Advisory on 
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the Use and Safety of Statins (Pasternak, Smith et al, 2002) have been adopted: 
Myopathy - a general term referring to any disease of muscles; Myalgia - muscle ache or 
weakness without creatine kinase (CK) elevation.  Myositis - muscle symptoms with 
increased CK levels.  Rhabdomyolysis - muscle symptoms with marked CK elevation 
(typically substantially greater than 10 times the upper limit of normal [ULN]) and with 
creatinine elevation (usually with brown urine and urinary myoglobin).   
The fact that statins are uncommonly associated with the development of myopathy is 
well accepted.  The incidence of myopathy is increased under equally well-accepted 
conditions, such as when the statin is used in combination with drugs such as 
cyclosporine, fibrates, macrolide antibiotics, certain antifungal drugs, and niacin.  Many 
of these associations relate to the use of drugs that antagonize metabolism through the 
cytochrome P-450 system, particularly the 3A4 isozyme.  While myopathy is rare, a 
more common adverse event is the development of myalgia, described as non-specific 
muscle aches or perceptions of weakness that do not involve any increase in CK.  In the 
placebo-controlled clinical trials with statins, the frequency of myalgia has been around 
5% and has been very similar between drug and placebo.  Nevertheless, many patients 
believe that their temporally associated myalgia is due to a statin, and it often returns on 
rechallenge.  Other patients can have mild-to-moderate elevations of CK symptoms 
involving muscle complaints.  Again, elevations may be non-specific, but a statin effect 
often cannot be ruled out.   
The PRIMO Study was a French nationwide observational survey of the risk factors and 
management of muscular side effects in patients receiving high-dosage statin treatment 
in general practice in France (Bruckert, Hayem et al, 2005).  A total of 
7,924 hyperlipidemic patients with age 18 - 75 years who were seen by their general 
practitioners (GPs) in regular outpatient visits were entered in the study.  GPs were 
asked to include the first three consecutive patients who satisfied the survey inclusion 
criteria during a period of up to 2 months following initiation of the study.  Patients were 
included if they had been prescribed high-dosage statin treatment (fluvastatin 80 mg; 
atorvastatin 40 or 80 mg; pravastatin 40 mg; or simvastatin 40 or 80 mg) for at least 
3 months prior to the study.  Patients were also included if their regimen had been 
adjusted (statin withdrawal or dose reduction) within the last 3 months due to muscular 
pain.  The risk factor analysis in PRIMO was consistent with the results of a preliminary 
study (Franc, Dejager et al, 2003), confirming that a personal or family history of 
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muscular symptoms, cramps, hypothyroidism and elevated CK levels were major risk 
factors for muscular symptoms during high-dosage statin therapy.   
In the PRIMO study population, 10.5% of patients on high-dosage statin therapy 
complained of muscle pain, a figure which is considerably higher than that reported 
previously for clinical trials but which is consistent with anecdotal experiences of 
practicing physicians.  The experience in PRIMO may be more representative than data 
from large scale placebo controlled studies where patients may have been excluded on 
the basis of age, diabetes, renal or hepatic impairment or a history of muscular 
symptoms or CK elevations.   
The results of the PRIMO study indicate that muscular symptoms associated with high 
dosage statin therapy may have a greater impact on the everyday life of patients than 
was previously thought.  Muscular pain was continuous in 25% of patients, while 39% of 
patients reported using an analgesic for pain relief of their muscular symptoms.  
Moreover, 38% of patients reported that their muscular symptoms prevented even 
moderate exertion during everyday activities, while 4% of patients suffered major 
disruption to their everyday life (being confined to bed or unable to work) due to 
muscular pain.  These findings are of considerable importance, because patients who 
experience adverse events during statin treatment are more likely to discontinue 
therapy. 
Asian patients frequently have heightened responses to therapeutic drugs, and statins in 
particular. As a consequence, the recommended drug doses are often lower in Asian 
countries than in Western countries. Studies have noted higher plasma levels of statins 
in Asians compared with Caucasians but not an increased safety risk  
(Wu, Sy et al, 2002). While the dosing of Japanese patients is different from the 
perspective of the highest dose used, only rosuvastatin is different when compared to 
American guidelines with respect to the lowest therapeutically effective dose. The below 
table recommended dose ranges for selected statins in the US and Japan  
(Saito, Hirata-Koizumi et al, 2005). 
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Recommended dose ranges for selected statins 
Statin 
Dose Range (mg/day) 
Japan 
United States 
Atorvastatin 
10–40 
10–80 
Fluvastatin 
20–60 
20–80 
Pravastatin 
10–20 
10–80 
Rosuvastatin 
2.5–20 
5–40 
Simvastatin 
5–20 
5–80 
Pitavastatin 
1-4 
1-4 
In summary, while there are anecdotal reports of increased statin intolerance in Asian 
populations due to increased pharmacokinetic exposure, and Asians appear to display 
higher plasma levels of rosuvastatin in comparison with Whites (Lee, Ryan et al, 2005), 
it is expected that statin intolerance will occur at similar rates as in Caucasian patients. 
Further, there is an unmet medical need for an effective non-statin agent that will get a 
significant proportion of Japanese patients to LDL-C goal. 
2.2 
Amgen Investigational Product Background 
Recycling of the hepatic cell surface LDL receptor (LDLR) plays a critical role in the 
maintenance of cellular and whole body cholesterol balance by regulating plasma LDL-C 
levels.  Recently it has been shown that Proprotein convertase subtilisin/kexin type 9 
(PCSK9) plays an important role in the recycling and regulation of LDLR 
(Horton et al, 2007; Brown and Goldstein, 2006).  PCSK9 is a member of the subtilisin 
family of serine proteases and is expressed predominantly in the liver, kidney, and 
intestine (Zaid et al, 2008).  Following secretion, it causes post-translational 
downregulation of hepatic cell surface LDLR by a mechanism that involves direct binding 
to the LDLR.  Downregulation of hepatic LDLR in turn leads to increased levels of 
circulating LDL-C.  Thus PCSK9 may represent a target for inhibition by novel 
therapeutics in the setting of dyslipidemia.  The rationale for such an approach is 
available from studies in preclinical models, and from human genetic data that provide 
strong validation for the role of PCSK9 in modulating LDL-C levels and the incidence of 
CHD in man.  These human studies have identified gain-of-function mutations in the 
PCSK9 gene that are associated with elevated serum LDL-C levels (> 300 mg/dL 
[approximately 7.8 mmol/L]) and premature CHD (Abifadel et al, 2003); and 
loss-of-function (LOF) mutations that are associated with low serum LDL-C levels 
(≤ 100 mg/dL [approximately 2.6 mmol/L]) (Cohen et al, 2005).  Strikingly, subjects with 
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heterozygous LOF mutations exhibit lower serum PCSK9 levels and as much as 
88% reduction in the incidence of CHD over a 15-year period compared with noncarriers 
of the mutations (Cohen et al, 2006).  Moreover, despite complete loss of PCSK9 and 
associated very low serum LDL-C levels (< 20 mg/dL [approximately 0.5 mmol/L]), the 
2 subjects who have been identified with compound heterozygote LOF mutations appear 
healthy (Hooper et al, 2007; Zhao et al, 2006). 
Evolocumab is a fully human monoclonal immunoglobulin (Ig) G2 that binds specifically 
to human PCSK9 and prevents the interaction of PCSK9 with LDLR.  Details of the 
biochemistry, nonclinical pharmacology, nonclinical pharmacokinetics (PK), and 
nonclinical toxicology with evolocumab are contained in the Investigator’s 
Brochure, 2016.  Evolocumab binds to human, monkey, and hamster PCSK9 with high 
affinity (Kd < 100 pM).  Evolocumab caused a dose-dependent inhibition of PCSK9 
binding to the LDLR and of PCSK9-mediated reduction in low-density lipoprotein (LDL) 
uptake in HepG2 cells (human hepatocellular carcinoma cell line) in culture.  In 
cynomolgus monkeys and in hamsters, in vivo administration of evolocumab resulted in 
reduced serum lipoprotein cholesterol levels in a dose-dependent manner.  Based on a 
comprehensive package of PK, pharmacodynamics (PD), and toxicology studies 
(Investigator’s Brochure, 2016), a program to develop evolocumab as a treatment for 
dyslipidemia was initiated. 
Evolocumab binds to human, monkey, and hamster PCSK9 with high affinity 
(Kd < 100 pM).  Evolocumab caused a dose-dependent inhibition of PCSK9 binding to 
the LDLR and of PCSK9-mediated reduction in low-density lipoprotein (LDL) uptake in 
HepG2 cells (human hepatocellular carcinoma cell line) in culture.  In cynomolgus 
monkeys and in hamsters, in vivo administration of evolocumab resulted in reduced 
serum lipoprotein cholesterol levels in a dose-dependent manner.  Based on a 
comprehensive package of PK, pharmacodynamics (PD), and toxicology studies 
(Investigator’s Brochure, 2016), a program to develop evolocumab as a treatment for 
dyslipidemia was initiated. 
2.3 
Non-Amgen Medicinal Product Background 
Ezetimibe 10mg tablets will be provided during study participation.  Ezetimibe will be 
over-encapsulated to maintain blinding.   
Ezetimibe is in a class of lipid-lowering compounds that selectively inhibits the intestinal 
absorption of cholesterol and related phytosterols.  Ezetimibe is approved in Japan for 
treatment of hypercholesterolemia, familial hypercholesterolemia, and homozygous 
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sitosterolemia. For patients with homozygous familial hypercholesterolemia, ezetimibe 
should be used as an adjunct to HMG-CoA reductase inhibitor and other lipid-lowering 
non-pharmacological treatments (eg, LDL apheresis) or when such treatments are 
unavailable. 
In the double blind placebo-controlled study of 100 Japanese hypercholesterolemia 
patients described in the label with a treatment duration of 12 weeks, LDL-C, total 
cholesterol, TG were reduced by 18.1%, 12.8% and 2.2%, respectively. HDL-C was 
increased by 5.9%.  
In the ezetimibe clinical studies of 504 Japanese patients described in the label, 
18.8% of patients on ezetimibe reported adverse reactions. The most commonly 
reported adverse reactions were constipation (3.0%), erythema (2.4%), diarrhea (2.2%), 
abdominal pain (2.0%), abdominal distension (1.6%), and nausea and vomiting (1.6%). 
Ezetimibe is contraindicated in the following circumstances: in combination with a statin 
in patients with severe liver dysfunction and in patients with a known hypersensitivity to 
ezetimibe. 
The recommended dose of ezetimibe is 10 mg once daily, administered after meal. 
2.4 
Rationale 
There is an established unmet medical need in Japan for patients with 
hypercholesterolemia who experience muscle-related side effects when using statins.  
Amgen is therefore seeking an indication for the use of evolocumab alone or in 
combination with a statin or other lipid-lowering therapies in patients with 
hypercholesterolemia who are statin-intolerant or unable to tolerate an effective dose of 
a statin. 
Subjects on low or atypical statin therapy must be on a stable dose for at least 
4 weeks prior to screening and throughout the blinded portion of the study; the 
dose cannot be adjusted during screening and for the duration of the study. 
This design provides a scientifically rigorous study to show the superiority of evolocumab 
over ezetimibe in Japanese patients who are intolerant to statins. Identified patients will 
be randomized 2:2:1:1 to QM evolocumab + PO placebo each day (QD), every 2 weeks 
(Q2W) evolocumab + PO placebo QD, QM SC placebo + ezetimibe QD, or Q2W SC 
placebo + ezetimibe QD for a head to head comparison evolocumab versus ezetimibe. 
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Long term exposure data will be provided by a 9-month open label extension where all 
patients will receive evolocumab in the same SC regimen (QM or Q2W) they were 
randomized to on Day 1. 
2.5 
Clinical Hypotheses 
The primary hypothesis is that evolocumab will be well tolerated and will result in greater 
reduction of LDL-C than ezetimibe, defined by the mean percent change from baseline 
at Weeks 10 and 12 and percent change from baseline at Week 12, in Japanese 
hypercholesterolemic subjects who are intolerant to statins or unable to tolerate an 
effective dose of a statin. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 3, multicenter, double-blind, randomized, ezetimibe controlled, parallel 
group study for evolocumab in hypercholesterolemic Japanese subjects unable to 
tolerate an effective dose of a statin.  Subjects who meet all inclusion/exclusion criteria 
will be randomized with an allocation ratio of 2:2:1:1 into 4 groups: QM 420 mg SC 
evolocumab + QD PO placebo, Q2W 140 mg SC evolocumab + QD PO placebo, QM 
SC placebo + QD 10 mg PO ezetimibe, Q2W SC placebo + QD 10 mg PO ezetimibe. 
Randomization will be stratified by screening LDL-C level and baseline statin use.  
Randomization should occur within 5 – 10 days of the screening LDL-C evaluation used 
to determine eligibility.  Subjects on low or atypical statin therapy must be on a stable 
dose for at least 4 weeks prior to the screening and throughout the blinded portion 
of the study; the dose cannot be adjusted during screening and for the duration of 
the study. 
For blinding purposes, every subject will receive investigational product (IP) SC and PO.  
Patients will be provided with evolocumab or placebo through the use of an autoinjector 
(AI) or Personal Injector. Depending on availability either a single Personal Injector or 
3 autoinjectors will be provided for monthly dosing. A single AI will be used for Q2W 
dosing.  Evolocumab and corresponding placebo will be administered at the study site or 
at appropriate non-clinic setting per Table 1 (Schedule of Assessments). PO placebo will 
be available to match PO ezetimibe through over-encapsulation. The SC IP dose 
frequencies of Q2W and QM will not be blinded. 
Following the Week 12 visit, all subjects will self-administer IP in the non-clinic setting; 
subjects will return to the clinical site at W24, W36, W48 and W52 for subsequent visits. 
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There will be an end of study phone call at W54 (Q2W subjects only) for any potential 
adverse events, serious adverse events, or adverse device effects. 
Central laboratory results of the lipid panel, ApoA1, ApoB, lipoprotein(a), and high 
sensitivity C-reactive protein (hsCRP) will be blinded during double-blind treatment.  
Investigators will be provided lipid results starting at week 24 until the end of study for 
each subject.  All lipid results from posttreament to week 24 will remain blinded until the 
unblinding of the clinical database. 
The study includes collection of biomarker samples, where approved by the institutional 
review board (IEC/IRB).  Administration of PO IP (ezetimibe or placebo) will end with the 
week 12 visit for all subjects. Following the week 12 visit, subjects should be treated to 
standard of care in addition to receiving open label evolocumab. 
Subjects will be encouraged to complete all planned visits regardless of their adherence 
to investigational product (IP) administration.  Formal review of the accumulating blinded 
data by an independent Data Monitoring Committee (DMC) will occur.  
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 40 sites in Japan will be selected to participate in this study.  Additional 
centers may be added. 
Sites that do not enroll subjects within 3 months of site initiation may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
The number of subjects will fulfill the planned sample size of 60 subjects. 
3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
Subject participation is anticipated to continue for 12 months (excluding screening 
period). There will be a 3 month double blind, randomized period with a 9-month open 
label extension. 
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3.5.2 
End of Study 
Primary Completion:  defined as the time when all the randomized subjects in the study 
have either completed the scheduled visits up to and including Week 24 or have early 
terminated from the study;  
End of Trial:  defined as the time when all enrolled subjects have either completed the 
scheduled visits or have early terminated from the study. 
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  Before any study-specific procedure, the appropriate written informed 
consent must be obtained.  Screening is initiated from the time of obtaining 
informed consent.  The screening period must be completed within 28 days. 
For a full list of eligibility criteria, please refer to Section 4.1. 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 
Inclusion Criteria 
101 
Subject who has provided informed consent/assent prior to initiation of 
any study-specific activities/procedures 
102 
Male or female ≥ 20 to ≤ 80 years of age, Japanese by 
self-identification, at signing of informed consent 
103 
Subject who is not at LDL-C goal as evidenced by the 2012 JAS 
management category and the following LDL-C levels by central 
laboratory at screening: 
a) 
Fasting LDL-C ≥ 100 mg/dL (2.59 mmol/L) for subjects with 
diagnosed CHD or are CHD risk equivalent or 
b) 
Fasting LDL-C ≥ 120 mg/dL (3.37 mmol/L) for subjects without 
diagnosed CHD or risk equivalent and Management Category III 
c) 
Fasting LDL-C ≥ 140 mg/dL (4.14 mmol/L) for subjects without 
diagnosed CHD or risk equivalent and Management Category II 
d) 
Fasting LDL-C ≥ 160 mg/dL (4.9 mmol/L) for subjects without 
diagnosed CHD or risk equivalent and Management Category I 
104 
Subject must have tried and failed at least 2 statins with failure to at least 
1 of the statins at an average daily dose at or below the following doses 
due to intolerable myopathy, ie, myalgia (muscle pain, ache, or weakness 
without CK elevation), myositis (muscle symptoms with increased CK 
levels), or rhabdomyolysis (muscle symptoms with marked CK elevation). 
For subjects that developed rhabdomyolysis, defined as CK > 10 x ULN, 
failure of only 1 statin at any dose is acceptable.  Symptoms must have 
resolved or improved when statin was discontinued or the dose was 
reduced. 
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• 
Atorvastatin 
10 mg 
• 
Fluvastatin 
20 mg 
• 
Pravastatin 
10 mg 
• 
Rosuvastatin 
2.5 mg 
• 
Simvastatin 
5 mg 
• 
Pitavastatin 
1 mg 
• 
For unlisted statins, the average daily dose should not exceed 
the lowest available recommended starting dose approved by 
the Japanese Ministry of Health, Labour and Welfare. 
105 
Subjects taking bile-acid sequestering resins and/or stanol, stanol 
esters, low (lowest available recommended starting dose approved 
by the Japanese Ministry of Health, Labour and Welfare) or atypical 
dose of statin must be on a stable dose for at least 4 weeks prior to 
screening.  No adjustments to statin (or other lipid lowering therapy) 
dose are allowed during screening and throughout study.  
EXCEPTION:  if subject is on ezetimibe at start of screening it must be 
discontinued for ≥ 1 week before LDL-C screening 
106 
Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory at 
screening 
4.1.2 
Exclusion Criteria 
201 
History of hemorrahagic stroke 
202 
Personal or family history of hereditary muscular disorders 
203 
NYHA III or IV heart failure, or last known left ventricular ejection fraction 
(LVEF) < 30% 
204 
Uncontrolled serious cardiac arrhythmia defined as recurrent and highly 
symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular 
response, or supraventricular tachycardia that are not controlled by 
medications, in the past 3 months prior to randomization 
205 
Myocardial infarction, unstable angina, percutaneous coronary 
intervention (PCI), coronary artery bypass graft (CABG) or stroke within 
3 months prior to randomization 
206 
Planned cardiac surgery or revascularization 
207 
Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c > 9.0%), newly 
diagnosed type 2 diabetes (within 6 months of randomization), or 
laboratory evidence of diabetes during screening (fasting serum glucose 
≥ 126 mg/dL [7.0 mmol/L] or HbA1c ≥ 6.5%) without prior diagnosis of 
diabetes 
208 
Uncontrolled hypertension defined as sitting systolic blood pressure 
(SBP) > 160 mmHg or diastolic BP (DBP) > 100 mmHg 
209 
Subject has taken in the last 4 weeks prior to LDL-C screening red yeast 
rice, > 200 mg/day niacin, or prescription lipid-regulating drugs 
(eg, fibrates and derivatives) other than low (lowest available 
recommended starting dose approved by the Japanese Ministry of 
Health, Labour and Welfare) or atypical dose of statins, ezetimibe, 
bile-acid sequestering resin, or stanols and stanol esters 
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Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 25 of 87 
210 
Subject who has taken a cholesterylester transfer protein (CETP) inhibitor 
in the last 12 months prior to LDL-C screening, such as: anacetrapib, 
dalcetrapib or evacetrapib 
211 
Treatment in the last 3 months prior to LDL-C screening with any of the 
following drugs: systemic cyclosporine, systemic steroids (eg, IV, 
intramuscular [IM], or PO) (Note: hormone replacement therapy is 
permitted), vitamin A derivatives and retinol derivatives for the treatment 
of dermatologic conditions (eg, Accutane); (Note: vitamin A in a 
multivitamin preparation is permitted) 
212 
Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid 
stimulating hormone (TSH) < 1.0 time the lower limit of normal or 
> 1.5 times the ULN, respectively, at screening.  Potential subjects with 
TSH < 1.0 time the lower limit of normal due to thyroid replacement 
therapy is not considered an exclusion 
213 
Moderate to severe renal dysfunction, defined as an estimated glomerular 
filtration rate (eGFR) < 30 ml/min/1.73m2 at screening 
214 
Active liver disease or hepatic dysfunction, defined as aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the 
ULN as determined by central laboratory analysis at screening 
215 
CK > 3 times the ULN at screening 
216 
Known active infection or major hematologic, renal, metabolic, 
gastrointestinal or endocrine dysfunction in the judgment of the 
investigator 
217 
Diagnosis of deep vein thrombosis or pulmonary embolism within 
3 months prior to randomization 
218 
Unreliability as a study participant based on the investigator's 
(or designee’s) knowledge of the subject (eg, alcohol or other drug abuse, 
inability or unwillingness to adhere to the protocol, or psychosis) 
219 
Female subject who has either (1) not used (an) acceptable method(s) of 
effective birth control (see below) for at least 1 month prior to screening 
and (2) is not willing to inform her partner of her participation in this 
clinical study and to use such (an) acceptable method(s) of effective birth 
control during treatment with SC IP (evolocumab/placebo) and for an 
additional 15 weeks after the end of treatment with SC IP 
(evolocumab/placebo), unless the female subject is sterilized or 
postmenopausal (see below); 
a. A female is considered of childbearing potential unless sterilized or 
postmenopausal with menopause defined as: 
i. 12 months of spontaneous and continuous amenorrhea in a 
female ≥ 55 years old, or 
ii. 12 months of spontaneous and continuous amenorrhea with a 
follicle-stimulating hormone (FSH) level > 40 IU/L (or according to 
the definition of “postmenopausal range” for the laboratory 
involved) in a female < 55 years old, or 
iii. The subject has undergone bilateral oophorectomy 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 26 of 87 
b. Acceptable methods of preventing pregnancy include not having 
intercourse (sexual abstinence), surgical contraceptive  
methods – (vasectomy of the male partner [and testing shows there is 
no sperm in the semen] or bilateral tubal ligation/occlusion), or use of 
hormonal birth control methods (pills, patches), intrauterine devices 
(IUDs), intrauterine hormonal-releasing system (IUS), male partner 
uses a condom with or without spermicide, use of a cervical cap, 
diaphragm, or contraceptive sponge with spermicide; or two (2) 
barrier methods (each partner must use one barrier method) with 
spermicide – males must use condom with spermicide; females must 
choose either diaphragm with spermicide, OR cervical cap with 
spermicide, OR contraceptive sponge with spermicide. 
c. Note: If additional medications are given during treatment which may alter 
the contraceptive requirements (these additional medications may require 
an increase in the number of contraceptive methods and/or length of time 
that contraception is to be utilized and/or length of time breastfeeding 
is to be avoided after the last dose of protocol-required therapies) the 
investigator is to discuss changes with the study subject.  
220 
Subject who is pregnant or breast feeding, or planning to become 
pregnant or breastfeed during treatment with SC IP 
(evolocumab/placebo) and/or within 15 weeks after the end of treatment 
with SC IP (evolocumab/placebo) 
221 
Subject who has previously received evolocumab or any other therapy to 
inhibit PCSK9 
222 
Subject who has any kind of disorder that, in the opinion of the 
investigator, may compromise the ability of the subject to give written 
informed consent and/or to comply with all required study procedures 
223 
Malignancy except non-melanoma skin cancers, cervical or breast ductal 
carcinoma in situ within the last 5 years 
224 
Subject who has known sensitivity or intolerance (eg, allergy or serious 
adverse reaction to ezetimibe) to any of the products or components to be 
administered during dosing 
225 
Subject who is likely to not be available to complete all protocol-required 
study visits or procedures, and/or to comply with all required study 
procedures (eg, Patient Reported Outcomes [PROs]) to the best of the 
subject and investigator’s knowledge 
226 
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 
227 
Currently enrolled in another investigational device or drug study, or less 
than 30 days since ending investigational device or drug study(ies), or 
receiving other investigational agent(s) or procedures 
CONFIDENTIAL 
 


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PPD


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 28 of 87 
The following are treatment groups (2:2:1:1 respectively): 
• 
Evolocumab SC, 420mg QM (3  AI/Pen or one Personal Injector) and 
PO placebo 10mg QD 
• 
Evolocumab SC, 140mg Q2W (1  AI/Pen) and PO placebo 10mg QD 
• 
Placebo SC 420mg QM (3  AI/Pen or one Personal Injector) and 
PO ezetimibe10mg QD 
• 
Placebo SC 140mg Q2W (1  AI/Pen) and PO ezetimibe10mg QD 
Once eligibility into the study has been confirmed, a site representative will make the 
randomization call to the IVRS/IWRS to assign a randomization number to the subject.  
The randomization call to the IVRS/IWRS is accomplished by entering the pertinent 
information detailed in the IVRS/IWRS user manual.  A confirmation email will be sent to 
the site to verify that the correct information has been entered and to confirm the 
assignment of a randomization number.  A subject will be considered randomized when 
a corresponding randomization number is assigned. 
Please refer to Section 5.2 below for details on when and how the randomization code 
may be broken.  The treatment assignment date is to be documented in the subject’s 
medical record and on the enrollment eCRF.  
5.2 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment should only be unblinded when knowledge of the 
treatment is essential for the further management of the subject on this study. Unblinding 
at the study site for any other reason will be considered a protocol deviation.   
Refer to the IVRS/IWRS manual for instructions on unblinding. 
The investigator is strongly encouraged to contact the Amgen Clinical Study Manager 
before unblinding any subject’s treatment assignment, but must do so within 1 working 
day after the event.   
6. 
TREATMENT PROCEDURES 
Evolocumab (AMG 145), placebo SC, ezetimibe PO, and placebo PO are IPs in this 
study.  An Investigational Product Instruction Manual (IPIM) containing detailed 
information regarding the storage, preparation, destruction, and administration of IP will 
be provided separately. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 29 of 87 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product(s) and/or matched placebo (except if required by 
local regulation) used in this study include(s): SC evolocumab (AMG 145) and SC 
Placebo.   
The Non-Amgen investigational product(s) used in this study include:  PO Ezetimibe 
10 mg, and PO Placebo.  
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab, matched placebo, and over-encapsulated ezetimibe.  
The medical device(s) used in this study include(s): Prefilled AI/Pen and Personal 
Injector. 
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Evolocumab (AMG 145) 
Evolocumab and respective placebo will be manufactured and packaged by Amgen Inc. 
and distributed using Amgen clinical IP distribution procedures.   
Evolocumab will be presented as a sterile, preservative-free solution in a single use, 
disposable, handheld mechanical (spring-based) 1.0 mL prefilled autoinjector/pen 
(AI/Pen) or 3.5 mL Personal Injector for fixed dose, subcutaneous injection.  The 
prefilled AI/Pen contains a 1.0 mL deliverable volume of 140 mg/mL evolocumab. 
The Personal Injector with prefilled cartridge assembly is a single-use, disposable, 
on-body electro-mechanical injection device that is co-packaged with a prefilled Crystal 
Zenith (CZ) cartridge assembly containing 3.5 mL deliverable volume of 120 mg/mL 
evolocumab.  
Evolocumab should be stored protected from light and according to the storage and 
expiration information (where required) provided on the label.  Evolocumab should be 
handled per the instructions provided in the IPIM.  AI/Pens should be checked for cracks 
or damage that may occur during shipment or if not handled properly.  Damaged product 
should not be administered.  Further details are provided in the IPIM.   
The box number of IP (active drug or placebo) is to be recorded on each subject’s Drug 
Administration eCRF.   
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 30 of 87 
6.2.1.1 
Dosage, Administration, and Schedule 
IP will be administered SC (evolocumab or matched placebo) in accordance with 
instructions in the IPIM.  For visits with IP administration at the study site, 
administration should be the last procedure to be performed during each visit.  The 
date and time of evolocumab or placebo will be recorded on the individual subject’s 
worksheet and eCRF.  After the first IP administration at the first dosing visit, subjects 
should be observed for at least 30 minutes before being discharged. 
Details of preparing and administering IP are included in the IPIM provided by Amgen at 
the start of the study.  The dosing schedule is described by a schema in the protocol 
synopsis. 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
There will be no dose adjustments in this study.  If, in the opinion of the investigator, a 
subject is unable to tolerate a specific dose of IP, that subject will discontinue IP but will 
continue to return for all other study procedures and measurements until the end of the 
study.   
Subjects who are late for a Scheduled Dose of Investigational Product 
Administration of IP should occur within the visit window for each scheduled visit.  IP 
must never be administered within less than 7 days of a previous dose.  If a subject 
arrives for a visit and IP was administered within less than 7 days prior the dose should 
not be administered, but all other study procedures should be conducted.  These 
subjects will receive their next SC IP administration as previously scheduled. 
Subjects who miss a Scheduled Dose of Investigational Product Completely 
Subjects randomized to SC IP administration (evolocumab or placebo) who completely 
miss a scheduled visit or IP administration will continue in the study and receive 
scheduled study drug at the next scheduled visit.  
6.2.2 
Non-Amgen Investigational Product(s)  
Non-Amgen investigational product(s) including ezetimibe 10mg PO and placebo PO will 
be used in this study.   
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 31 of 87 
6.2.2.1 
Non-Amgen Investigational Product Ezetimibe 
6.2.2.1.1 
Dosage, Administration, and Schedule 
Ezetimibe 10 mg tablets will be administered orally, once daily, with or without food, at a 
time convenient to the subject.  To enable blinding of the PO IP, ezetimibe will be 
supplied as over-encapsulated 10 mg tablets.   
Ezetimibe 10mg is an approved drug for the treatment of patients with 
hypercholesterolemia, familial hypercholesterolemia, and homozygous sitosterolemia 
(ZETIA® [ezetimibe]). 
Subjects who miss a dose of ezetimibe will be advised to take the missed dose as soon 
as they can however subjects should not take more than one dose of ezetimibe per day; 
subsequent doses will be taken at the usual time.  However, if the next scheduled dose 
would be due in less than 12 hours, the subject will be advised to omit the missed dose 
entirely and to take the next dose at the normal time.  Consult the IPIM for additional 
information on ezetimibe. 
6.2.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
No dosage adjustment is necessary in patients with mild hepatic or renal impairment.  
No dosage adjustment is necessary in geriatric patients.  Additional details regarding 
ezetimibe are provided in the IPIM. 
6.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransaminase [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. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 32 of 87 
6.3.1 
Criteria for Permanent Discontinuation of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
Amgen investigational product and other protocol required therapies should be 
discontinued permanently and the subject should be followed according to the 
recommendations in Appendix A (Additional Safety Assessment Information) for possible 
drug-induced liver injury (DILI), if ALL of the criteria below are met:  
• 
TBL > 2x upper limit of normal (ULN) or INR > 1.5 
• 
AND increased AST or ALT from the relevant baseline value as specified below:  
Baseline AST or ALT value 
AST or ALT elevation 
< ULN 
> 3x ULN 
• 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to: 
− 
Hepatobiliary tract disease 
− 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
− 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.   
− 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
− 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
− 
Alpha-one antitrypsin deficiency 
− 
Alcoholic hepatitis 
− 
Autoimmune hepatitis  
− 
Wilson’s disease and hemochromatosis 
− 
Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH)  
− 
Non-hepatic causes (eg, rhabdomyolysis, hemolysis) 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 33 of 87 
6.3.2 
Criteria for Conditional Withholding of Amgen Investigational 
Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of Amgen 
investigational product outlined above and have no underlying liver disease, and 
eligibility criteria requiring normal transaminases and TBL at baseline or subjects with 
underlying liver disease and baseline abnormal transaminases, the following rules are 
recommended for withholding of Amgen investigational product and other 
protocol-required therapies:  
• 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
Any 
> 8x ULN at any time 
Any 
> 5x ULN but < 8x ULN for ≥ 2 weeks 
Any 
> 5x ULN but < 8x ULN and unable to adhere to enhanced 
monitoring schedule 
Any 
> 3x ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).   
• 
OR: TBL > 3x ULN at any time 
• 
OR: ALP > 8x ULN at any time>> 
Evolocumab should be withheld pending investigation into alternative causes of DILI.  If 
investigational product(s) is withheld, the subject is to be followed according to 
recommendations in Appendix A for possible DILI.  Rechallenge may be considered if an 
alternative cause for impaired liver tests (ALT, AST, ALP) and/or elevated TBL, is 
discovered and the laboratory abnormalities resolve to normal or baseline 
(Section 6.3.3).   
6.3.3 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then evolocumab should be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation 
(as described in Section 6.3.1) should never be rechallenged. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 34 of 87 
6.4 
Concomitant Therapy, Diet, and Exercise  
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.7. 
Subjects should maintain their current regimen of diet and exercise.  Subjects will be 
required to refrain from unaccustomed intensive exercise (eg, heavy lifting or long runs) 
48 hours prior to each visit. 
6.5 
Medical Devices 
Amgen SC IP (evolocumab/placebo) will be administered per prefilled AI/Pen or 
3.5 mL Personal Injector, provided by Amgen.  Additional details regarding the use of the 
AI/Pen or Personal Injector is provided in the IPIM and in the Instructions for Use (IFU) 
brochure.  Other medical devices (eg, syringes, sterile needles, alcohol prep pads), 
which are not considered test articles, may be used in the conduct of this study as 
part of standard care.  These devices are commercially available are not usually 
provided or reimbursed by Amgen (except, for example, if required by local regulation).  
The investigator will be responsible for obtaining supplies of these devices.   
6.6 
Product Complaints, Including Device Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution to market or clinic by 
either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  This includes any drug(s), device(s), or combination product(s) 
provisioned and/or repackaged/modified by Amgen.  Drugs or devices include 
evolocumab/placebo, prefilled AI/Pen, and Personal Injector. 
Concerns or irregularities about the packaging, appearance or usage of the prefilled 
AI/Pen or Personal Injector must be reported to Amgen within 24 hours of discovery or 
notification of the concern or irregularity.  Should any such concerns or irregularities 
occur please do not use the prefilled AI/Pen or Personal Injector until Amgen confirms 
that it is permissible to use. 
Examples of potential product complaints that need to be reported to Amgen include, but 
are not limited to: 
• 
broken container or cracked container, 
• 
subject or healthcare provider cannot appropriately use the product despite training 
(eg, due to malfunction of the prefilled AI/Pen or Personal Injector), 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 35 of 87 
• 
missing labels, illegible labels, incorrect labels, and/or suspect labels,  
• 
change in IP appearance, for example color change or visible presence of foreign 
material, 
• 
unexpected quantity or volume, for example amount of fluid in the prefilled AI/Pen or 
Personal Injector, or 
• 
evidence of tampering or stolen material. 
If possible, please have the prefilled AI/Pen or Personal Injector available for 
examination when making a product complaint.  Maintain the prefilled AI/Pen or 
Personal Injector at appropriate storage conditions until further instructions are received 
from Amgen.   
The investigator is responsible for ensuring that all product complaints, including device 
complaints, observed by the investigator or reported by the subject that occur after 
signing of the informed consent form (ICF) through 30 days after the last dose of IP or 
EOS, whichever is later, are reported to Amgen within 24 hours of discovery or 
notification of the product and/or device complaint.  
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 
6.7 
Excluded Treatments and/or Procedures During Study Period  
The following treatments are not permitted during the study: 
• 
Prescription lipid regulating medications (eg, non-study ezetimibe, or fibrates and 
derivatives) 
• 
However, the following agents are allowed: 
− 
bile-acid sequestering resin 
− 
stanol and stanol esters 
− 
Please note:  subjects on a low (lowest available recommended starting 
dose approved by the Japanese Ministry of Health, Labour and Welfare) or 
atypical dose of statins may continue their current dose if the subject has 
taken it for at least 4 weeks prior to the screening; new statin initiations, 
and/or dose adjustments are not permitted during screening or the study 
itself. 
• 
Red yeast rice, niacin > 200 mg per day 
• 
Any other drug that significantly affects lipid metabolism (eg, systemic cyclosporine, 
systemic steroids [IV, IM, or PO] (Note: hormone replacement therapy is permitted, 
vitamin A derivatives and retinol derivatives for the treatment of dermatologic 
conditions [eg, Accutane]).  Vitamin A as part of a multivitamin preparation is 
permitted. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 36 of 87 
• 
Prescribed amphetamines, or amphetamine derivatives, and weight loss 
medications. 
Should there be a clinical need to prescribe one of these treatments, the investigator 
should call the Amgen Medical Monitor to discuss. 
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 37 of 87 
Table 1.  Schedule of Assessments 
Study Day / Timepoint 
Screening & 
Placebo 
Run-in 
D1 
Visit 
W2 
Visit 
W4 
W6 
W8 
Visit 
W10 
Visit 
W12 
Visit 
W24 
Visit 
W36 
Visit 
W48 
Visit 
W52 
Visit 
W54i 
EOS Phone 
Call 
General Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (sitting BP, HR, RR, Temp) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Review for AE/SAE/ADEa 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary instruction 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Body weight, waist circumference  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipidsb 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
ApoA1, ApoB, Lp(a) 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
PK, PCSK9 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
Chemistry
c Hematologyd 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
HbA1c 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers (blood) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Anti-evolocumab antibodies 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
HCV antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV viral load (only HCV positive 
patients) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Serum pregnancy; FSH 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Urine pregnancye 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Urinalysisf 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
SC Placebo Run-in 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Q2W SC IP on-site 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Q2W SC IP non-clinic settingg 
 
 
 
X 
X 
 
 
 
X 
X 
X 
 
 
Q2W IP Dispensation/Accountability 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
QM SC IP on-site 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
QM SC IP non-clinic settingh 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
QM IP Dispensation/Accountability 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
PO IP Dispensation/Accountability 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Footnotes defined on next page of the table 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 38 of 87 
a Review for adverse events, serious adverse events, and adverse device effects.  Adverse events possibly related to study procedures, adverse device effects, and 
serious adverse events are collected during the screening period from signing of the ICF through 30 days post last dose of IP or EOS, whichever is later. 
b Fasting lipids: Total cholesterol, HDL-C, LDL-C, Triglycerides, VLDL-C, non-HDL-C. 
c Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Total protein, Albumin, Calcium, Magnesium, Phosphorus, Fasting Glucose, BUN or Urea, Creatinine, Uric acid, Total 
bilirubin, Direct bilirubin, CK, Alk phos, LDH, AST (SGOT), ALT (SGPT). 
d Hematology: RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, WBC, Platelets 
e Prior to on-site SC IP administration, female subjects of childbearing potential should have urine pregnancy test performed. 
f Urinalysis: Specific gravity, pH, Blood, Protein, Glucose, Bilirubin, WBC, RBC, Epithelial cells, Bacteria, Casts, Crystals. 
g Subjects on Q2W dosing will continue non-clinic setting injections after the Week 12 visit per dosing regimen. 
h Subjects on QM dosing will continue non-clinic setting injections after the Week 12 visit per dosing regimen. 
i For Q2W subjects only. 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 39 of 87 
7.2 
General Study Procedures  
Written informed consent must be obtained and will be implemented before protocol 
specific procedures are carried out.  The risks and benefits of participating in the study 
will be verbally explained to each potential subject prior to entering into the study.  The 
study includes collection of biomarker samples, where approved by the independent 
ethics committee and/or institutional review board (IEC/IRB) .  If IP is administered 
during a study visit, administration should occur after completion of vital signs and blood 
draw procedures, as applicable. 
Subjects must be fasting for ≥ 9 hours before each study visit where fasting laboratory 
samples are obtained.  If the subject is not fasting for any screening visit or the 
Day 1 visit, no laboratory samples should be collected and the subject must return as 
soon as possible in a fasting state for the visit.  If the subject is not fasting for any visit 
with evaluation of lipids after study Day 1, all visit procedures, including investigational 
product administration, should be completed except for the fasting lipid blood sample.  
Please make sure to schedule an extra visit for the fasting sample collection, if possible 
within the window for the respective visit. 
The Analyte Listing below outlines the specific analytes for serum chemistry, 
hematology, urinalysis, and other testing to be conducted. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 40 of 87 
Analyte Listing 
Chemistry  
Sodium 
Potassium 
Chloride 
Bicarbonate  
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Fasting Glucose 
BUN or Urea 
Creatinine 
Uric acid 
Total bilirubin 
Direct bilirubin 
CK 
Alk phos 
LDH 
AST (SGOT) 
ALT (SGPT) 
Urinalysis 
Specific gravity 
pH 
Blood 
Protein  
Glucose 
Bilirubin 
WBC 
RBC 
Epithelial cells 
Bacteria 
Casts 
Crystals 
Hematology 
RBC 
Hemoglobin 
Hematocrit 
MCV  
MCH 
MCHC 
RDW 
WBC 
Platelets 
Other Labs 
Fasting lipids 
• 
Total cholesterol 
• 
HDL-C 
• 
LDL-C 
• 
Triglycerides 
• 
VLDL-C 
• 
non-HDL-C 
ApoA1 
ApoB 
hsCRP 
LP(a) 
Anti-evolocumab 
antibodies 
PCSK9 
HbA1c 
Pregnancy test 
(females of 
childbearing potential) 
FSH (if needed per 
exclusion 219) 
TSH 
PK & biomarkers 
HCV antibody* 
HCV viral load** 
*HCV antibodies are measured before initiating treatment with investigational product in 
subjects at high risk for HCV infection and in subjects with ALT or AST > 2x ULN at any 
time during screening.  Conditions that may place subjects at high risk for HCV 
infection include the following: 
• 
Ever injected illegal drugs 
• 
Received clotting factors made before 1987  
• 
Received blood/organs before July 1992 or were exposed to blood known to be 
infected with HCV 
• 
Were ever on chronic hemodialysis  
• 
Are known to be infected with HIV 
• 
Have a known HCV-infected sexual partner  
**Viral load will be tested at the time points indicated in Schedule of Assessments, only 
in subjects who are positive for HCV. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 41 of 87 
Some laboratory results may inadvertently unblind investigators to treatment assignment 
to evolocumab.  Central laboratory results of the lipid panel, ApoA1, ApoB, Lp(a), and 
hsCRP posttreatment to week 24 will not be reported to the investigator until the 
unblinding of the clinical database.  Investigators should not perform non-protocol testing 
of these analytes during a subject’s study participation from first administration of IP until 
at least 24 weeks after the subject’s first blinded IP administration.  Investigators will be 
informed if triglycerides are > 1000 mg/dL (11.3 mmol/L) so that appropriate subject 
follow-up can be initiated. 
7.2.1 
Placebo Run-in 
In order to reduce the burden of unnecessary procedures on subjects who subsequently 
elect not to participate in the study or continue with study procedures, all subjects will 
enter a placebo run-in period to confirm tolerance of SC administration prior to 
randomization.  This placebo run-in period can be started before or after venipuncture 
procedures for the study and will consist of SC administration of placebo consisting of 
the AI/Pen.  This administration will follow the same procedures as injections of IP using 
the AI/Pen during the treatment period.  Further details will be provided in the IPIM. 
7.2.2 
Screening Enrollment and/or Randomization 
The following procedures are to be completed during the screening period of subjects at 
time points designated in the Schedule of Assessments: 
• 
Informed Consent Form signed  
• 
Medical history 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects.  
Adverse events possibly related to study procedures, adverse device effects, and 
serious adverse events are collected during the screening period from signing of 
the ICF 
• 
Documentation of concomitant medications  
• 
Dietary instruction: subject will be counseled on the importance of maintaining a 
“heart-healthy” diet throughout the course of the study; medication compliance 
reminder 
• 
Physical exam 
• 
Body height 
• 
Body weight and waist circumference   
• 
Central Laboratory Assessments (as per Schedule of Assessments): 
 
Blood draw for fasting lipids (≥ 9 hour fasting sample), chemistry (including 
fasting glucose), CK, hematology, HbA1c, TSH, (Note: eGFR will be calculated 
by the central laboratory and will be provided to the site for eligibility 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 42 of 87 
determination), blood draws for hepatitis C virus (HCV) antibodies in subjects at 
high risk for, or with history of, HCV infection and in subjects with AST or 
ALT > 2x ULN at any time during screening, serum FSH (only if required to 
ensure menopause in a female subject by central laboratory) 
 
Serum pregnancy (females of childbearing potential only) 
 
Urine sample for urinalysis  
• 
Subject instruction on self-administration of evolocumab for AI/Pen or 
Personal Injector 
• 
AI/Pen placebo injection (does not need to be repeated for rescreening) 
7.2.3 
Treatment 
7.2.3.1 
Visit Day 1 (Randomization) 
The following procedures should be conducted at this visit for all subjects unless 
specified otherwise. 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Provide dietary instruction: subject will be counseled on the importance of 
maintaining a “heart-healthy” diet throughout the course of the study; medication 
compliance reminder 
• 
Randomization treatment assignment via IVR/IWR system 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
• 
SF-36 
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
Anti-evolocumab Antibodies 
• 
HCV viral load (only HCV positive individuals) 
• 
Subject instruction on self-administration of evolocumab for AI/Pen or 
Personal Injector 
• 
SC IP administration on-site under site staff supervision (all subjects) 
• 
PO IP dispensing 
7.2.3.2 
Visit/Week 2 
The following procedures should be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Provide dietary instruction: subject will be counseled on the importance of 
maintaining a “heart-healthy” diet throughout the course of the study; medication 
compliance reminder 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 43 of 87 
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
• 
PO IP tablet count  
• 
SC IP dispensing with instructions for use at week 4 (all subjects) and week 6 
(Q2W subjects only) 
• 
Subject instruction on self-administration of evolocumab for AI/Pen or 
Personal Injector 
• 
SC IP administration on-site (Q2W subjects only) 
• 
PO IP dispensing 
7.2.3.3 
Week 4 
The following procedure will be performed in a non-clinic setting, eg, self-administration 
by the subject in the non-clinic setting (± 3 days): 
• 
Administration of SC IP 
7.2.3.4 
Week 6 (Subjects on Q2W SC IP Only) 
The following procedure will be performed in a non-clinic setting, eg, self-administration 
by the subject in the non-clinic setting (± 3 days): 
• 
Administration of SC IP to subjects randomized to Q2W SC IP 
7.2.3.5 
Visit/Week 8 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Provide dietary instruction: subject will be counseled on the importance of 
maintaining a “heart-healthy” diet throughout the course of the study; medication 
compliance reminder 
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
• 
PO IP tablet count 
• 
SC IP administration on-site (all subjects) 
• 
PO IP dispensing 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 44 of 87 
7.2.3.6 
Visit/Week 10 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Provide dietary instruction: subject will be counseled on the importance of 
maintaining a “heart-healthy” diet throughout the course of the study; medication 
compliance reminder 
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
• 
PO IP tablet count 
• 
SC IP administration on-site (Q2W subjects only) 
• 
SC IP dispensing (if applicable) 
• 
PO IP dispensing 
7.2.3.7 
Visit/Week 12 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Provide dietary instruction: subject will be counseled on the importance of 
maintaining a “heart-healthy” diet throughout the course of the study; medication 
compliance reminder 
• 
Physical exam 
• 
SF-36 
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
• 
PO IP tablet count 
• 
SC IP dispensing (subjects will continue with the previously assigned dosing 
regimen of Q2W or QM) 
• 
Remind patients to discontinue blinded oral IP 
• 
SC IP administration on-site (all subjects) 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 45 of 87 
7.2.3.8 
Visit/Week 24 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
SC IP dispensing (subjects will continue with the previously assigned dosing 
regimen of Q2W or QM) 
7.2.3.9 
Visit/Week 36 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
SC IP dispensing (subjects will continue with the previously assigned dosing 
regimen of Q2W or QM) 
7.2.3.10 
Visit/Week 48 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
SC IP dispensing (subjects will continue with the previously assigned dosing 
regimen of Q2W or QM) 
7.2.3.11 
Visit/Week 52 
The following procedures will need to be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
• 
Vital signs (eg, sitting blood pressure, heart rate, respiratory rate, temperature) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
• 
Documentation of concomitant medications  
• 
Physical exam 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 46 of 87 
• 
Body weight and waist circumference   
• 
Central Laboratory Assessments as Per Schedule of Assessments 
• 
SC IP accountability 
7.2.4 
Safety Follow-up / End of Study Phone Call/Week 54 (± 3 days) 
• 
Review for adverse events, serious adverse events, and adverse device effects 
(Q2W subjects only) 
• 
Documentation of concomitant medications (Q2W subjects only) 
7.2.5 
Standardization of Study Procedures 
7.2.5.1 
Measurement of Vital Signs 
The following measurements must be performed: Systolic/Diastolic Blood Pressure, 
Heart Rate, Respiratory Rate, and Temperature. 
Subject must be in a seated and calm state for at least 5 minutes before blood pressure 
assessments are conducted.  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. 
7.2.5.2 
Waist Circumference 
Subjects should wear minimal clothing to ensure that the measuring tape is correctly 
positioned.  Subjects should stand erect with the abdomen relaxed, arms at the sides, 
feet together and with their weight equally divided over both legs.  To perform the waist 
measurement, the lowest rib margin is first located and marked with a pen.  The iliac 
crest is then palpated in the midaxillary line, and also marked.  It is recommended to 
apply an elastic tape horizontally midway between the lowest rib margin and the iliac 
crest, and tie firmly so that it stays in position around the abdomen about the level of the 
umbilicus.  The elastic tape thus defines the level of the waist circumference, which can 
then be measured by positioning the measuring tape over the elastic tape.  Subjects are 
asked to breathe normally, and to breathe out gently at the time of the measurement to 
prevent them from contracting their muscles or from holding their breath.  Measurements 
should be performed using the same procedure throughout the study.  The reading is 
taken to the nearest centimeter or ½ inch and entered in the source document. 
7.2.5.3 
Lipid Measurements  
Only the screening LDL-C concentration will be reported to the site for the eligibility 
decision.  For subjects who are rescreened, data from the first screening period will not 
be used for the analysis.  Central laboratory results of the lipid panel, as well as ApoA1, 
ApoB, lipoprotein(a), and high sensitivity C-reactive protein (hsCRP) will be blinded 
CONFIDENTIAL 
 


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CCI


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 49 of 87 
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 
PCSK9 inhibition, the dose response and/or prediction of response to evolocumab or 
anti-evolocumab antibodies, 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 biomarker development, or other exploratory studies are 
not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 50 of 87 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the options for continuation of the Schedule of Assessments (Table 1) and 
collection of data, including endpoints and adverse events.  The investigator must 
document the change to the Schedule of Assessments (Table 1) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment, or Study 
8.3.1 
Reasons for Removal From Treatment  
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, protocol-specified 
criteria, pregnancy) 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 51 of 87 
• 
death 
• 
lost to follow-up 
• 
decision by Sponsor (other than subject request, safety concern, lost to follow-up) 
8.3.2 
Reasons for Removal From Study 
• 
Reasons for removal of a subject from the study are: 
o decision by sponsor  
o withdrawal of consent from study 
o death 
o lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Adverse Events 
9.1.1 
Definition of Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study 
is not considered an adverse event.   
Resolution of the adverse event will be captured using the applicable eCRF. 
An adverse device effect is any adverse event related to the use of a combination 
product or a medical device.  Adverse device effects include adverse events resulting 
from insufficient or inadequate instructions for use, adverse events resulting from any 
malfunction of the device, or adverse events resulting from use error or from intentional 
misuse of the device. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 52 of 87 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.2 
Definition of Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria: 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention. 
9.2 
Reporting of Adverse Events 
9.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment and all adverse events 
possibly related to study procedures and all adverse device effects from signing of the 
informed consent through the safety follow-up/end of study (End of Study Phone Call) 
are reported using the applicable eCRF (eg, Event eCRF). 
The investigator must assign the following adverse event attributes: 
• 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity [and/or toxicity per protocol], 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 53 of 87 
• 
Assessment of relatedness to SC IP (evolocumab or placebo), PO IP (ezetimibe or 
placebo), Amgen medical device(s): prefilled Autoinjector/Pen (AI/Pen) or 3.5 mL 
Personal Injector and 
• 
Action taken 
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE).  The grading scale used in this study is described in  
Appendix A.  The investigator must assess whether the adverse event is possibly related 
to SC IP (evolocumab or placebo) or PO IP (ezetimibe or placebo).  This relationship is 
indicated by a “yes” or “no” response to the question:  Is there a reasonable possibility 
that the event may have been caused by SC IP or PO IP?  Relatedness means that 
there are facts or reasons to support a relationship between IP and the event. 
The investigator must assess whether the adverse event is possibly related to the  
prefilled AI/Pen or Personal Injector Amgen device used to administer SC IP.  The 
relationship is indicated by a “yes” or “no” response to the question: Is there a 
reasonable possibility that the event may have been caused by the Amgen device? 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, device(s) and/or procedure (including any screening procedure(s)).  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
reasonable possibility that the event may have been caused by a study activity 
(eg, administration of investigational product,  protocol-required therapies, device(s)), 
and/or procedure”?  
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  In general, abnormal laboratory 
findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
The Investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 54 of 87 
9.2.2 
Reporting Procedures for Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 30 days after the last day of the dosing interval of investigational 
product(s) or end of study, whichever is later, are recorded in the subject’s medical 
record and are submitted to Amgen.  All serious adverse events must be submitted to 
Amgen within 24 hours following the investigator’s knowledge of the event via the 
applicable eCRF.  
The serious adverse event must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the applicable eCRF (eg, the Safety Report 
Form).  If the electronic data capture (EDC) system is unavailable to the site staff to 
report the Serious Adverse Event, the information is to be reported to Amgen via an 
electronic Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of 
the investigator’s knowledge of the event.  See Appendix B for a sample of the electronic 
Serious Adverse Event Contingency Report Form.  For EDC studies where the first 
notification of a Serious Adverse Event is reported to Amgen via the eSerious Adverse 
Event Contingency Report Form, the data must be entered into the EDC system when 
the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to  
SC IP (evolocumab or placebo) or PO IP (ezetimibe or placebo). This relationship is 
indicated by a “yes” or “no” response to the question:  Is there a reasonable possibility 
that the event may have been caused by SC IP or PO IP?  Relatedness means that 
there are facts or reasons to support a relationship between IP and the event. 
The investigator must assess whether the serious adverse event is possibly related to 
the prefilled AI/Pen or Personal Injector Amgen device used to administer SC IP.  The 
relationship is indicated by a “yes” or “no” response to the question: Is there a 
reasonable possibility that the event may have been caused by the Amgen device? 
The investigator must assess whether the serious adverse event is possibly related to 
any study-mandated activity or procedure.  This relationship is indicated by a “yes” or 
“no” response to the question:  “Is there a reasonable possibility that the event may have 
been caused by a study activity/procedure”?  
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 55 of 87 
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  The investigator 
may be asked to provide additional follow-up information, which may include a discharge 
summary or extracts from the medical record.  Information provided about the serious 
adverse event must be consistent with that recorded on the applicable eCRF 
(eg, Event eCRF). 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Investigators 
will receive notification of related serious adverse events reports sent to regulatory 
authorities in accordance with local requirements.   
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice.  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
After the protocol-required reporting period defined above or after end of study, the 
investigator does not need to actively monitor subjects for serious adverse events.  
However, if the investigator becomes aware of a serious adverse event after this 
protocol required reporting period or after end of study, the investigator will report the 
event to Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period or 
after end of study will be captured within the safety database as clinical trial cases for 
the purposes of expedited reporting. 
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 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 56 of 87 
EDC has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form (eSAE Contingency Report Form). 
9.3 
Pregnancy and Lactation Reporting 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking evolocumab report the pregnancy to Amgen as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of evolocumab and for an 
additional 15 weeks after the end of treatment with evolocumab, report the pregnancy to 
Amgen as specified below.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be 
requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
If a lactation case occurs while the female subject is taking evolocumab, report the 
lactation case to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of evolocumab through an additional 
15 weeks after the end of treatment with evolocumab, report the lactation case to 
Amgen, as specified below.    
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up 
with the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 57 of 87 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates  
10.1.1 
Study Endpoints 
Co-Primary Endpoints: 
• 
Mean percent change from baseline in LDL-C at weeks 10 and 12, and 
• 
Percent change from baseline in LDL-C at week 12. 
Co-Secondary Efficacy Endpoints: 
Co-secondary endpoints of the means at weeks 10 and 12 and at week 12 for: 
Tier 1 
• 
Change from  baseline in LDL-C 
• 
LDL-C response (LDL-C < 70 mg/dL [1.8 mmol/L]) 
• 
Percent change from  baseline in total cholesterol 
• 
Percent change from  baseline in non-HDL-C  
• 
Percent change from  baseline in ApoB 
• 
Percent change from  baseline in the total cholesterol/HDL-C ratio 
• 
Percent change from  baseline in ApoB/ApoA1 ratio 
Tier 2 
• 
Percent change from  baseline in Lp(a) 
• 
Percent change from  baseline in triglycerides  
• 
Percent change from  baseline in HDL-C 
• 
Percent change from  baseline in VLDL-C 
Tertiary Efficacy Endpoints 
• 
Mean percent change from baseline in ApoA1 at weeks 10 and 12 
• 
Percent change from baseline in ApoA1 at week 12 
Exploratory Endpoints 
• 
Subject incidence of non-coronary revascularization 
• 
Observed values, change and percent change from baseline at each scheduled 
visit in each of the following parameters: 
o LDL-C 
o Total cholesterol 
o non-HDL-C 
o ApoB 
o Total cholesterol/HDL-C ratio 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 58 of 87 
o ApoB/ApoA1 ratio 
o VLDL-C 
o HDL-C 
o ApoA1 
o Triglycerides 
o Lp(a) 
• 
hsCRP at each scheduled assessment 
• 
PCSK9 change from baseline at each scheduled assessment 
Safety Endpoints 
• 
Subject incidence of adverse events 
• 
Safety laboratory values at each scheduled visit 
• 
Incidence of anti-evolocumab antibody (binding and neutralizing) formation 
Pharmacokinetics Endpoints 
• 
Serum concentration of evolocumab at selected time points 
10.1.2 
Analysis Sets 
Full Analysis Set 
The full analysis set (FAS) includes all randomized subjects who received at least 
1 dose of IP in the double blind treatment period. This analysis set will be used in both 
efficacy and safety analyses for the double blind treatment period.  
Generally, in efficacy analyses, subjects will be grouped according to their randomized 
treatment group assignment and by pooled treatment. In safety analyses, subjects will 
be grouped according to their randomized treatment group assignment with the 
exception: if a subject receives treatment throughout the study is different than the 
randomized treatment group assignment, then the subject will be grouped by the actual 
treatment group. 
Completer Analysis Set 
The completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled IP in the double blind treatment period and have observed values for the 
co-primary endpoints. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 59 of 87 
Open Label Extension Period Analysis Set 
The open label extension period analysis set (OLEAS) includes subjects in the FAS who 
received at least 1 dose of evolocumab in the open label extension period. This analysis 
set will be used in both efficacy and safety analyses for the open label extension period.  
10.1.3 
Covariates and Subgroups 
Baseline covariates include, but are not limited to: 
• 
Stratification factors: 
o Screening LDL-C level: < 180 mg/dL [4.7 mmol/L] vs. ≥ 180 mg/dL 
o Baseline statin use: yes vs. no 
The following baseline covariates may be used for subgroup or covariate analyses with 
the subgroups as specified or in their original format: 
• 
Age: < 65 years, ≥ 65 years; < 75 years, ≥ 75 years  
• 
Sex 
• 
LDL-C: < baseline median, ≥ baseline median 
• 
PCSK9 level: < baseline median, ≥ baseline median 
• 
Baseline lipid regulating medications use: yes vs. no 
10.2 
Sample Size Considerations 
The planned sample size for the comparison between evolocumab and ezetimibe is 
40 (20 in Q2W and QM each) and 20 subjects (10 in Q2W and QM each), respectively 
(60 total).  The primary analysis will require the 2-sided tests of each co-primary 
endpoint to be significant at a level of 0.05.  From the global phase 3 study 20110116, 
the treatment effect of evolocumab compared to ezetimibe for reduction from baseline in 
LDL-C at week 12 is at least 37.6% (32.9%, 42.2%) and for the mean of week 10 and 
12, 36.9% (31.6%, 42.3%).  Assuming 5% of randomized subjects do not receive any IP 
and with a common standard deviation (SD) of approximately 20%, this study has at 
least 93% power to detect a treatment effect of 20% or greater reduction for each of the 
co-primary endpoints in testing the superiority of evolocumab over ezetimibe, based on a 
two-sided t-test with significance level 0.05. 
As the co-primary endpoints are correlated, there is at least 85% (93% x 93%) power to 
detect significant treatment effects of the co-primary endpoints.  The power calculation is 
derived using nQuery version 7.01. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 60 of 87 
10.3 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
Blinded individuals will not have access to unblinded information until the study is 
formally unblinded.  Unblinding and potentially unblinding information should not be 
distributed to the study team, investigators or subjects prior to the study being formally 
unblinded except as specified (eg, Section 5.2 and Section 9.2.2). 
The independent DMC members, and Independent Biostatistical Group (IBG) will have 
access to treatment assignments and subject level data from the clinical trial database. 
Amgen staff members who are involved in randomization, biological sample 
management, and performing PK and anti-evolocumab antibody assay analysis will have 
treatment assignment information, but will not have access to subject level data from the 
clinical trial database. 
10.4 
Planned Analyses 
10.4.1 
Data Monitoring Committee (DMC) 
An external independent DMC has been established to formally review the accumulating 
data from this and other completed and ongoing studies with evolocumab to ensure 
there is no avoidable increased risk for harm to subjects.  The independent DMC is 
chaired by an external academic cardiologist who is an expert in lipids and clinical trials.  
Analyses for the DMC are provided by the Independent Biostatistical Group (IBG), which 
is external to Amgen.  Details are provided in the DMC charter. 
10.4.2 
Primary Analysis 
To evaluate efficacy and safety of 12 weeks of evolocumab compared with ezetimibe 
and summarize 12 weeks of data from the open-label extension (weeks 12 to 24), 
the primary analysis will be performed when all the randomized subjects in the study 
have either completed the scheduled visits up to and including Week 24 or have early 
terminated from the study. At that time, the database of the study will be cleaned, 
processed and a snapshot will be taken; the study will also be unblinded. 
10.4.3 
Final Analysis 
The final analysis will be conducted when all enrolled subjects have either completed the 
scheduled visits or have early terminated from the study. At that time, the database of 
study will be cleaned, processed and a snapshot will be taken. The long-term safety and 
efficacy of evolocumab will be assessed.  
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 61 of 87 
10.5 
Planned Methods of Analysis 
10.5.1 
General Considerations 
Based on the snapshot for the primary analysis, efficacy and safety analyses will be 
performed on the FAS. Unless otherwise specified, the FAS will be the default analysis 
set for the primary analysis and data will be summarized by randomized treatment group 
assignment and by pooled frequency for evolocumab and pooled ezetimibe.  The 
treatment effect of evolocumab compared to ezetimibe will be evaluated for all 
efficacy endpoints through the Week 12 visit.  In addition, descriptive analyses from 
the open-label extension (weeks 12 to 24) will be performed on OLEAS. 
Based on the snapshot for the final analysis, long-term efficacy and safety analyses will 
be performed on OLEAS and the analyses will be descriptive. 
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized. 
Summary statistics for continuous variables will include the number of subjects, mean, 
median, Q1, Q3, standard deviation or standard error, minimum, and maximum. For 
categorical variables, the frequency and percentage will be given. 
Missing data will not be imputed for safety endpoints. 
Multiplicity Adjustment Method 
Methods of adjusting for multiplicity due to multiple endpoints (co-primary and 
co-secondary efficacy endpoints) in order to preserve the familywise error rate at 0.05 
are described in the diagram below. 
CONFIDENTIAL 
 


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Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 63 of 87 
10.5.2 
Primary Efficacy Endpoint 
Primary Analysis 
To assess the co-primary endpoints of the mean percent change from baseline at 
weeks 10 and 12 and the percent change from baseline at week 12 in LDL-C, a 
repeated measures linear effects model will be used to compare the efficacy of 
evolocumab (pooled Q2W and QM) with pooled ezetimibe. The repeated measures 
model will include terms of treatment group, stratification factor of screening LDL-C level, 
scheduled visit, and the interaction of treatment group with scheduled visit. Missing 
values will not be imputed when the repeated measures linear effects model is used. 
Sensitivity Analysis 
To evaluate the robustness of the primary analysis results, sensitivity analyses will be 
performed as follows: 
• 
The primary analysis will be repeated using the CAS 
• 
Non-parametric analyses (Quade, 1979) 
Additional Analyses 
The co-primary endpoints will also be assessed within each dose frequency using dose 
frequency matched control (ie, evolocumab Q2W SC plus placebo PO QD vs. ezetimibe 
QD plus placebo Q2W SC; evolocumab QM SC plus placebo PO QD vs. ezetimibe QD 
plus placebo QM SC) and pooled ezetimibe (ie, evolocumab Q2W vs. pooled ezetimibe; 
evolocumab QM vs. pooled ezetimibe) 
In addition, the difference between the evolocumab Q2W and evolocumab QM groups 
will be estimated. 
10.5.3 
Secondary Efficacy Endpoints 
The statistical model and testing of the tier 1 co-secondary efficacy endpoints will be 
similar to the primary analysis of the co-primary endpoints. The co-secondary efficacy 
endpoints of LDL-C response will be analyzed using the Cochran-Mantel Haenszel 
(CMH) test adjusted by stratification factor. 
Analyses of the tier 2 co-secondary efficacy endpoints will use the same analysis model 
as the tier 1 endpoints, and the testing will use a union-interaction test. 
Multiplicity adjustment procedures are defined in Section 10.5.1. 
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10.5.4 
Tertiary Efficacy Endpoints Analyses 
Analysis of the tertiary efficacy endpoints will be similar to the primary analysis of the 
co-primary endpoints. No multiplicity adjustment will be applied. 
10.5.5 
Safety Endpoints 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  Tables of fatal adverse events, serious adverse events, 
treatment-related adverse events, adverse events leading to withdrawal from 
investigational product, and significant treatment-emergent adverse events will also be 
provided. Subject-level data may be provided instead of tables if the subject incidence is 
low. 
Safety Laboratory Parameters 
The analyses of key safety laboratory endpoints will include summary statistics at each 
scheduled visit by treatment group. Shifts in grades of safety laboratory values between  
the baseline and the maximum post-baseline grade will be tabulated by treatment group. 
Laboratory shift tables for certain analytes will be provided using the CTCAE v.4 toxicity 
criteria. 
Vital Signs and Physical Measurement 
The analyses of vital signs and physical measurement will include summary statistics at 
each scheduled visit by treatment group. 
Concomitant Medications 
Concomitant medications of interest will be summarized for each treatment group. 
Anti-AMG 145 antibodies 
The incidence and percentages of subjects who develop anti-evolocumab antibodies 
(binding and neutralizing) at any time will be tabulated. 
10.5.6 
Exploratory Endpoint Analyses 
Exploratory endpoints related to lipid parameters will be summarized by treatment group 
and by scheduled visit using descriptive statistics. 
Non-coronary revascularizations will be collected on the eCRF.  Subject incidence of 
exploratory endpoint events will be summarized for each treatment group. 
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Date:  21 March 2017 
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11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent document is to be prepared in the 
language(s) of the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject after adequate explanation of the 
aims, methods, anticipated benefits, and potential hazards of the study and before any 
protocol-specific screening procedures or any investigational product(s) is/are 
administered.   
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  The original 
signed informed consent form is to be retained in accordance with institutional policy, 
and a copy of the signed consent form is to be provided to the subject. 
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. 
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
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written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB/IEC approval /renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the 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 date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with Federal regulations/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. 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
If Amgen amends the protocol, agreement from the Investigator must be obtained.  The 
IRB/IEC must be informed of all amendments and give approval.  The investigator must 
send a copy of the approval letter from the IRB/IEC to Amgen. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study’s completion or early termination and send a copy of the notification to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on eCRFs will be included on the Amgen Delegation of Authority Form. 
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. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
• 
Subject files containing completed eCRFs, informed consent forms, and subject 
identification list 
• 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
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• 
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. 
• 
Non-investigational product(s) and or medical device(s) documentation, as 
applicable. 
In addition, all original source documents supporting entries in the eCRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Amgen Clinical Monitor is responsible for verifying the eCRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The Clinical Monitor is to have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs. 
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. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Compliance Auditing function 
(or designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy 
storage areas, laboratories) and review of study-related records will occur to evaluate 
the study conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the eCRFs must be maintained and 
readily available. 
• 
Updates to eCRFs will be automatically documented through the software’s “audit 
trail”. 
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• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries and/or site notifications are created in the EDC system 
database for site resolution and closed by Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this electronic data 
capture study.  This signature indicates that investigator inspected or reviewed the 
data on the eCRF, the data queries, and the site notifications, and agrees with the 
content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database, as documented in the Study Specific Self Evident Corrections 
Plan.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (eg, same results sent twice with the same 
date with different visit-week 4 and early termination) and clarifying “other, specify” if 
data are provided (eg, race, physical examination).  Each investigative site will be 
provided a list of the types of corrections applied to study data at the initiation of the trial 
and at study closeout.   
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments, the investigator can search publically available records 
[where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  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. 
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen encourages the formation of 
a publication committee consisting of several investigators and appropriate Amgen staff, 
the governance and responsibilities of which are set forth in a Publication Charter.  The 
committee is expected to solicit input and assistance from other investigators and to 
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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 Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (International Committee of Medical Journal 
Editors, 2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part 
of the work are appropriately investigated and resolved.  Authors should meet 
conditions 1, 2, 3, and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
Abifadel M, Varret M, Rabes J-P, et al.  Mutations in PCSK9 cause autosomal dominant 
hypercholesterolemia.  Nat Genet.  2003;34:154-156. 
Amgen.  AMG 145 Investigator’s Brochure, edition 9.2.  28 September 2016. 
Brown MS, Goldstein JL.  Biomedicine.  Lowering LDL--not only how low, but how long? 
Science.  2006;311:1721-1723. 
Bruckert E, Hayem G, Dejager S, Yau C, Begaud B.  Mild to moderate muscular 
symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study.  
Cardiovasc Drugs Ther.  2005;19(6):  403-414. 
Cohen J, Pertsemlidis A, Kotowski IK, et al.  Low LDL cholesterol in individuals of 
African descent resulting from frequent nonsense mutations in PCSK9.  Nat Genet.  
2005;37:161-165. 
Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH.  Sequence variations in PCSK9, low 
LDL, and protection against coronary heart disease.  N Engl J Med.  
2006;354:1264-1272. 
Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G.  A comprehensive 
description of muscle symptoms associated with lipid-lowering drugs.  Cardiovasc Drugs 
Ther.  2003;17(5-6):459-465. 
Hochberg Y.  A sharper Bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75:800-802. 
Horton JD, Cohen JC, Hobbs HH.  Molecular biology of PCSK9:  its role in LDL 
metabolism.  Trends Biochem Sci.  2007;32:71-77.  
Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR.  The C679X mutation in PCSK9 is 
present and lowers blood cholesterol in a Southern African population.  Atherosclerosis.  
2007;193:445-448. 
Lee E, Ryan S, Birmingham B, et al.  Rosuvastatin pharmacokinetics and 
pharmacogenetics in white and Asian subjects residing in the same environment. 
Clin Pharmacol Ther.  2005;78(4):330-341. 
Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C.  
American College of Cardiology, American Heart Association, National Heart, Lung, and 
Blood Institute.  ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins.  
Stroke 2002;33(9):2337-2341. 
Quade D.  Using weighted rankings in the analysis of complete blocks with additive 
block effects.  J Am Stat Assoc.  1979;74:680–683. 
Saito M, Hirata-Koizumi M, Urano T, Miyake S, Hasegawa R.  A literature search on 
pharmacokinetic drug interactions of statins and analysis of how such interactions are 
reflected in package inserts in Japan.  J Clin Pharm Ther.  2005;30(1):21-37. 
Wiens BL.  A fixed sequence Bonferroni procedure for testing multiple endpoints.  
Pharmaceut Statist.  2003;2:211–215.  
Wu CC, Sy R, Tanphaichitr V, Hin AT, Suyono S, Lee YT.  Comparing the efficacy and 
safety of atorvastatin and simvastatin in Asians with elevated low-density 
lipoprotein-cholesterol--a multinational, multicenter, double-blind study.  J Formos Med 
Assoc.  2002;101(7):478-487. 
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Zaid A, Roubtsova A, Essalmani R, et al.  Proprotein convertase subtilisin/kexin type 9 
(PCSK9):  hepatocyte-specific low-density lipoprotein receptor degradation and critical 
role in mouse liver regeneration.  Hepatology.  2008;48:646-654. 
Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al.  Molecular characterization of loss-of-
function mutations in PCSK9 and identification of a compound heterozygote.  Am J Hum 
Genet.  2006;79:514-23. 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) Version 4.0 for 
AE grading and information.  The CTCAE is available at the following link:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Drug-induced Liver Injury Reporting & Additional Assessments Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation according to the criteria specified in Section 6.3 require 
the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours 
of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded) 
• 
The appropriate eCRF (eg, Event eCRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to the Amgen.  
• 
Other events of hepatotoxicity and potential DILI are to be reported as serious 
adverse events if they meet the criteria for a serious adverse event defined in 
Section 9.2.2. 
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 
Section 6.3.1 and Section 6.3.2 or who experience AST or ALT elevations >3 x ULN are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  Assessments that are to be performed during this period 
include:  
• 
Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours  
• 
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: 
• 
Obtain complete blood count (CBC) with differential to assess for eosinophilia 
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• 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis 
• 
Obtain serum acetaminophen (paracetamol) levels 
• 
Obtain a more detailed history of:  
 
Prior and/or concurrent diseases or illness 
 
Exposure to environmental and/or industrial chemical agents  
 
Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
 
Prior and/or concurrent use of alcohol, recreational drugs and special 
diets 
 
Concomitant use of medications (including non-prescription medicines 
and herbal and dietary supplements), plants, and mushrooms 
• 
Obtain viral serologies 
• 
Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
• 
Perform appropriate liver imaging if clinically indicated 
• 
Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected  
• 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
• 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal.  The “close observation period” is to 
continue for a minimum of 4 weeks after discontinuation of all 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 corresponding eCRFs. 
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Appendix B.  Sample Electronic Serious Adverse Event Contingency Reporting 
Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
  
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Appendix D.  Japan Atherosclerosis Society (JAS) Guidelines for the Diagnosis 
and Prevention of Atherosclerotic Cardiovascular Diseases in Japan (2012) 
From: https://www.jstage.jst.go.jp/article/jat/20/6/20_15792/_pdf 
 
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Amendment 3.0 
Protocol Title:  A Double-blind, Randomized, Multicenter Study to Evaluate the 
Safety and Efficacy of Evolocumab, Compared With Ezetimibe, in 
Hypercholesterolemic Japanese Subjects Unable to Tolerate an Effective Dose of 
a HMG-CoA Reductase Inhibitor due to Muscle Related Side Effects 
GAUSS-4:  Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin 
Intolerant Subjects 
 
Amgen Protocol Number Evolocumab 20140234 
 
Amendment Date: 
21 March 2017 
Rationale: 
This is Amendment 3 for Evolocumab Study 20140234.  Amendment 2 for this protocol 
was not implemented and therefore, the changes captured in this document reflect 
changes made from Amendment 1 to Amendment 3. 
The primary change to the protocol is to clarify the timing for the primary analysis from 
week 12 to week 24 per agreement with the Japanese Pharmaceuticals and Medical 
Devices Agency (PMDA).  The analyses will include the  
• 
Double-blind phase efficacy and safety evaluations (week 12 data) 
• 
Open-label extension phase safety data (week 12 to week 24 data) 
• 
Combined double-blind and open-label extension phase efficacy data 
In addition, the following were clarified to ensure alignment with study procedures: 
• 
Update acceptable methods of birth control that are now available in Japan 
• 
Removal of Vitamin E from Section 7.2 as this analyte is neither collected nor 
analyzed 
• 
Removal of adjudication of events as CV events were never adjudicated in GAUSS 4 
(a memo was distributed to the sites during startup activities, prior to any subjects 
being enrolled) 
• 
Removal of collection of “CV events” as these are already captured as adverse 
events or serious adverse events 
• 
Clarify that prior to on-site subcutaneous (SC) investigational product (IP) 
administration, female subjects of childbearing potential should have a urine 
pregnancy test performed 
• 
Include information about providing subject instruction for self-administration of 
AI/Pen or Personal Injector 
• 
Add low or atypical statin therapy that is ongoing at study entry can be continued 
throughout the study 
• 
The screening period is initiated from the time of obtaining informed consent and 
must be completed within 28 days 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 2 of 30 
• 
Observation is required only after first IP administration visit 
• 
Align safety definitions and reporting procedures with current protocol template 
(including pregnancy and lactation notification worksheets) 
• 
Administration, typographical, and formatting changes were made throughout the 
protocol 
CONFIDENTIAL 
 


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Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 4 of 30 
Section:  Title page 
Add:   
Amendment 2: 
11 April 2016 (not distributed) 
Amendment 3: 
21 March 2017 
Section:  Protocol Synopsis, Study Design, Paragraph 1 
Replace:   
Subjects on low or atypical statin dose will continue to take the statin without any dose 
adjustment for the duration of the blinded portion of the study. 
With:   
Subjects on low or atypical statin therapy must be on a stable dose for at least 
4 weeks prior to screening and throughout the blinded portion of the study; the dose 
cannot be adjusted during screening and for the duration of the study. 
Section:  Protocol Synopsis, Study Design, Paragraph 4 
Add:   
There will be an end of study phone call at W54 (Q2W subjects only) for any potential 
adverse events/serious adverse events/adverse device effects. 
Section:  Protocol Synopsis, Study Design, Paragraph 5 
Delete:   
The study includes collection of biomarker samples, where approved by the institutional 
review board (IEC/IRB).  The last collection of lipids for the primary analysis  will occur at 
week 12.  End of study (EOS) for subjects is by contact (eg, phone call) from the site at 
week 54 for any potential Adverse Events or Serious Adverse Events. 
Section:  Protocol Synopsis, Study Design, Paragraph 6 
Replace:   
The study includes adjudication of deaths and specific cardiovascular (CV) events by an 
independent Clinical Events Committee (CEC) and formal review of the accumulating 
blinded data by an independent Data Monitoring Committee (DMC). 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 5 of 30 
With: 
The study includes a formal review of the accumulating blinded data by an independent 
Data Monitoring Committee (DMC). 
Section:  Protocol Synopsis, Summary of Subject Eligibility Criteria, Paragraph 1 
Add:   
Males and females, ≥ 20 to ≤ 80 years of age, Japanese by self-identification, are 
eligible for this study. 
Section:  Protocol Synopsis, Summary of Subject Eligibility Criteria, Paragraph 2 
Add:   
Symptoms must have resolved or improved when statin was discontinued or the dose 
was reduced. 
Section:  Protocol Synopsis, Statistical Considerations, General Considerations, 
Paragraph 1 
Replace: 
When all the randomized subjects in the study have either completed the scheduled 
visits up to and including Week 12 or have early terminated from the study, a primary 
analysis will be performed, where efficacy and safety of 12 weeks of evolocumab 
compared with ezetimibe will be evaluated on the full analysis set (FAS) that includes all 
randomized subjects who received at least 1 dose of IP in the double blind treatment 
period.  The superiority of evolocumab to ezetimibe will be assessed for all efficacy 
endpoints. 
With: 
When all the randomized subjects in the study have either completed the scheduled 
visits up to and including Week 24 or have early terminated from the study, a primary 
analysis will be performed.  Efficacy and safety of 12 weeks of evolocumab compared 
with ezetimibe will be evaluated on the full analysis set (FAS) that includes all 
randomized subjects who received at least 1 dose of IP in the double blind treatment 
period.  In addition, the 12 weeks of data from the open-label extension 
(weeks 12 to 24) will also be summarized.  The treatment effect of evolocumab 
compared to ezetimibe will be evaluated for all efficacy endpoints through the Week 
12 visit.  In addition, descriptive analyses from the open-label extension 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 6 of 30 
(weeks 12 to 24) will be performed on the open label extension analysis set 
(OLEAS). 
Section:  Protocol Synopsis, Statistical Considerations, Safety Analyses 
Replace: 
Safety summaries will include the subject incidence of adverse events, summaries of 
laboratory parameters and anti-evolocumab. Deaths and major CV events will be 
adjudicated by an independent CEC. Subject incidence of adjudicated events will be 
summarized for each treatment group. 
With: 
Safety summaries will include the subject incidence of adverse events, summaries of 
laboratory parameters and anti-evolocumab antibodies. 
Section:  Protocol Synopsis, End of section 
Add:   
Data Element Standards 
Version/Date: 
Version 5/20 March 2015 
Section:  Study Glossary 
Delete: 
Abbreviation or Term 
Definition/Explanation 
ADE 
Adverse device effect 
AE 
Adverse event 
CEC 
Clinical events committee 
Q2W 
Q2W is defined as every 2 weeks with a window of ± 3 days for each 
visit 
QM 
QM is defined as every 4 weeks with a window of ± 7 days for each 
visit 
SAE 
Serious adverse event 
Section:  2.4 Rationale, Paragraph 2 
Replace: 
Patients on low or atypical statin dose will continue to take the statin without any dose 
adjustment for the duration of the study. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 7 of 30 
With: 
Subjects on low or atypical statin therapy must be on a stable dose for at least 
4 weeks prior to screening and throughout the blinded portion of the study; the 
dose cannot be adjusted during screening and for the duration of the study. 
Section:  3.1 Study Design, Paragraph 1 
Replace: 
Patients on low or atypical statin dose will continue to take the statin without any dose 
adjustment for the duration of the blinded portion of the study. 
With: 
Subjects on low or atypical statin therapy must be on a stable dose for at least 
4 weeks prior to the screening and throughout the blinded portion of the study; the 
dose cannot be adjusted during screening and for the duration of the study. 
Section:  3.1 Study Design, Paragraph 3 
Add: 
There will be an end of study phone call at W54 (Q2W subjects only) for any potential 
adverse events, serious adverse events, or adverse device effects. 
Section:  3.1 Study Design, Paragraph 5 
Delete:   
The study includes collection of biomarker samples, where approved by the institutional 
review board (IEC/IRB).  The last collection of lipids for the primary analysis will occur at 
week 12.  EOS for subjects is by contact (eg, phone call) from the site at week 54 for 
any potential AEs or SAEs. 
Section:  3.1 Study Design, Paragraph 6 
Replace: 
The study includes adjudication of deaths and specific cardiovascular (CV) events by an 
independent Clinical Events Committee (CEC) and formal review of the accumulating 
blinded data by an independent Data Monitoring Committee (DMC).  
With: 
Formal review of the accumulating blinded data by an independent Data Monitoring 
Committee (DMC) will occur.  
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 8 of 30 
Section:  3.5.2 End of Study 
Replace: 
Primary Completion:  defined as the time when all the randomized subjects in the study 
have either completed the scheduled visits up to and including Week 12 or have early 
terminated from the study; 
With: 
Primary Completion:  defined as the time when all the randomized subjects in the study 
have either completed the scheduled visits up to and including Week 24 or have early 
terminated from the study; 
Section:  4 Subject Eligibility, Paragraph 1 
Add: 
Screening is initiated from the time of obtaining informed consent.  The screening 
period must be completed within 28 days. 
Section:  4 Subject Eligibility, Paragraph 2 
Delete: 
For a full list of eligibility criteria, please refer to Section 4.1. and Section 4.1.2 
Section:  4.1.1 Inclusion Criteria, Criterion 102 
Add: 
102 
Male or female ≥ 20 to ≤ 80 years of age, Japanese by self-identification, at 
signing of informed consent 
Section:  4.1.1 Inclusion Criteria, Criterion 104 
Add: 
104 
Subject must have tried and failed at least 2 statins with failure to at least 1 of the 
statins at an average daily dose at or below the following doses due to intolerable 
myopathy, ie, myalgia (muscle pain, ache, or weakness without CK elevation), 
myositis (muscle symptoms with increased CK levels), or rhabdomyolysis 
(muscle symptoms with marked CK elevation). For subjects that developed 
rhabdomyolysis, defined as CK > 10 x ULN, failure of only 1 statin at any dose is 
acceptable.  Symptoms must have resolved or improved when statin was 
discontinued or the dose was reduced. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 9 of 30 
Section:  4.1.1 Inclusion Criteria, Criterion 104, Bullet 7 
Replace: 
• 
For unlisted statins, the average daily dose should not exceed the lowest available 
starting dose approved by PMDA or applicable country regulatory authority. 
With: 
• 
For unlisted statins, the average daily dose should not exceed the lowest available 
recommended starting dose approved by the Japanese Ministry of Health, 
Labour and Welfare. 
Section:  4.1.1 Inclusion Criteria, Criterion 105 
Replace: 
105 
Lipid lowering therapy has been stable prior to LDL-C screening for at least 
4 weeks if currently on a bile-acid sequestering resin and/or stanol; if subject is 
on ezetimibe at start of screening it must be discontinued for ≥ 1 week before 
LDL-C screening 
With: 
105 
Subjects taking bile-acid sequestering resins and/or stanol, stanol esters, low 
(lowest available recommended starting dose approved by the Japanese 
Ministry of Health, Labour and Welfare) or atypical dose of statin must be 
on a stable dose for at least 4 weeks prior to screening.  No adjustments to 
statin (or other lipid lowering therapy) dose are allowed during screening 
and throughout study.  EXCEPTION:  if subject is on ezetimibe at start of 
screening it must be discontinued for ≥ 1 week before LDL-C screening 
Section:  4.1.2 Exclusion Criteria, Criterion 209 
Add: 
209 
Subject has taken in the last 4 weeks prior to LDL-C screening red yeast rice, 
> 200 mg/day niacin, or prescription lipid-regulating drugs (eg, fibrates and 
derivatives) other than low (lowest available recommended starting dose 
approved by the Japanese Ministry of Health, Labour and Welfare) or 
atypical dose of statins, ezetimibe, bile-acid sequestering resin, or stanols and 
stanol esters 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 10 of 30 
Section:  4.1.2 Exclusion Criteria, Criterion 219, Items b and c 
Add: 
b. 
Acceptable methods of preventing pregnancy include not having intercourse 
(sexual abstinence), surgical contraceptive  
methods – (vasectomy of the male partner [and testing shows there is no 
sperm in the semen] or bilateral tubal ligation/occlusion), or use of hormonal 
birth control methods (pills, patches), intrauterine devices (IUDs), intrauterine 
hormonal-releasing system (IUS), male partner uses a condom with or 
without spermicide, use of a cervical cap, diaphragm, or contraceptive 
sponge with spermicide; or two (2) barrier methods (each partner must use 
one barrier method) with spermicide – males must use condom with spermicide; 
females must choose either diaphragm with spermicide, OR cervical cap with 
spermicide, OR contraceptive sponge with spermicide. 
c. 
Note: If additional medications are given during treatment which may alter the 
contraceptive requirements (these additional medications may require an 
increase in the number of contraceptive methods and/or length of time that 
contraception is to be utilized and/or length of time breastfeeding is to be 
avoided after the last dose of protocol-required therapies) the investigator is to 
discuss changes with the study subject.  
Section:  4.1.2 Exclusion Criteria, Criterion 221 
Delete: 
221 
Subject who has previously received evolocumab or any other investigational 
therapy to inhibit PCSK9 
Section:  4.1.2 Exclusion Criteria, Criterion 224 
Add: 
224 
Subject who has known sensitivity or intolerance (eg, allergy or serious adverse 
reaction to ezetimibe) to any of the products or components to be administered 
during dosing 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 11 of 30 
Section:  5 Subject Enrollment, Paragraph 1 
Add: 
Screening is initiated from the time of obtaining informed consent.  The screening 
period must be completed within 28 days. 
Section:  5.1 Randomization/Treatment Assignment, Paragraph 1 
Replace: 
Randomization will be stratified by screening LDL-C concentration (< 180 mg/dL 
[4.66 mmol/L] vs. ≥ 180 mg/dL) at baseline. 
With: 
Randomization will be stratified by screening LDL-C concentration (< 180 mg/dL 
[4.66 mmol/L] vs. ≥ 180 mg/dL) and baseline statin use. 
Section:  5.1 Randomization/Treatment Assignment, Paragraph 3 
Replace: 
A confirmation fax will be sent to the site to verify that the correct information has been 
entered and to confirm the assignment of a randomization number. 
With: 
A confirmation email will be sent to the site to verify that the correct information has 
been entered and to confirm the assignment of a randomization number. 
Section:  6 Treatment Procedures 
Add: 
Evolocumab (AMG 145), placebo SC, ezetimibe PO, and placebo PO are IPs in this 
study.  An Investigational Product Instruction Manual (IPIM) containing detailed 
information regarding the storage, preparation, destruction, and administration of IP will 
be provided separately. 
Section:  6.1 Classification of Product(s) and/or Medical Device(s), Paragraph 3 
Add: 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of evolocumab, matched placebo, and over-encapsulated ezetimibe. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 12 of 30 
Section:  6.2.1.1 Dosage, Administration, and Schedule, Paragraph 1 
Replace: 
IP administration by SC injection at each visit must be done after vital signs and blood 
draw procedures, if applicable.  The date and time of evolocumab or placebo  will be 
recorded on the individual subject’s worksheet and/or eCRF.  After IP administration at 
each dosing visit, subjects should be observed for at least 30 minutes before being 
discharged. 
With: 
For visits with IP administration at the study site, administration should be the last 
procedure to be performed during each visit.  The date and time of evolocumab or 
placebo will be recorded on the individual subject’s worksheet and eCRF.  After the first 
IP administration at the first dosing visit, subjects should be observed for at least 
30 minutes before being discharged. 
Section:  6.5 Medical Devices, Paragraph 1 
Add: 
Amgen SC IP (evolocumab/placebo) will be administered per prefilled AI/Pen or 
3.5 mL Personal Injector, provided by Amgen.  Additional details regarding the use of the 
AI/Pen or Personal Injector is provided in the IPIM and in the Instructions for Use (IFU) 
brochure.  Other medical devices (eg, syringes, sterile needles, alcohol prep pads), 
which are not considered test articles, may be used in the conduct of this study as 
part of standard care.  These devices are commercially available are not usually 
provided or reimbursed by Amgen (except, for example, if required by local regulation). 
Section:  6.6 Product Complaints, Including Device Complaints, Paragraph 1 
Add: 
This includes any drug(s), device(s), or combination product(s) provisioned 
and/or repackaged/modified by Amgen.  Drugs or devices include 
evolocumab/placebo, prefilled AI/Pen and Personal Injector. 
Section:  6.6 Product Complaints, Including Device Complaints, Paragraph 5 
Add: 
The investigator is responsible for ensuring that all product complaints, including device 
complaints, observed by the investigator or reported by the subject that occur after 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 13 of 30 
signing of the informed consent form (ICF) through 30 days after the last dose of IP or 
EOS, whichever is later, are reported to Amgen within 24 hours of discovery or 
notification of the product and/or device complaint. 
Section:  6.7 Excluded Treatments and/or Procedures During Study Period, 
Paragraph 1, Bullet 1 
Replace: 
• 
Prescription lipid regulating medications (eg, non-study ezetimibe, or fibrates and 
derivatives), other than bile-acid sequestering resin, or stanol and stanol esters 
With: 
• 
Prescription lipid regulating medications (eg, non-study ezetimibe, or fibrates and 
derivatives) 
• 
However, the following agents are allowed: 
− 
bile-acid sequestering resin 
− 
stanol and stanol esters 
− 
Please note:  subjects on a low (lowest available recommended starting 
dose approved by the Japanese Ministry of Health, Labour and Welfare) or 
atypical dose of statins may continue their current dose if the subject has 
taken it for at least 4 weeks prior to the screening; new statin initiations, 
and/or dose adjustments are not permitted ruing screening or the study 
itself. 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 14 of 30 
Section:  7.1 Schedule of Assessments, Table1 
Replace: 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 15 of 30 
With: 
Study Day / Timepoint 
Screening & 
Placebo 
Run-in 
D1 
Visit 
W2 
Visit 
W4 
W6 
W8 
Visit 
W10 
Visit 
W12 
Visit 
W24 
Visit 
W36 
Visit 
W48 
Visit 
W52 
Visit 
W54i 
EOS Phone 
Call 
General Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs (sitting BP, HR, RR, Temp) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Review for AE/SAE/ADEa 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapy 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary instruction 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Body weight, waist circumference  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Body height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Central Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipidsb 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
ApoA1, ApoB, Lp(a) 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
PK, PCSK9 
 
X 
X 
 
 
 
X 
X 
 
 
 
X 
 
Chemistry
c Hematologyd 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
hsCRP 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
HbA1c 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers (blood) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Anti-evolocumab antibodies 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
HCV antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV viral load (only HCV positive 
patients) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Serum pregnancy; FSH 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Urine pregnancye 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Urinalysisf 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
SC Placebo Run-in 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Q2W SC IP on-site 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Q2W SC IP non-clinic settingg 
 
 
 
X 
X 
 
 
 
X 
X 
X 
 
 
Q2W IP Dispensation/Accountability 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
QM SC IP on-site 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
QM SC IP non-clinic settingh 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
QM IP Dispensation/Accountability 
 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
 
PO IP Dispensation/Accountability 
 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 16 of 30 
Section:  7.1 Schedule of Assessments, Table1, Footnotes 
Replace: 
Footnotes defined on next page. 
a SAEs are collected from signing of the ICF through 30 days post last dose of IP or EOS, whichever is later (only AEs possibly related to study procedures 
from signing of the ICF) 
b Fasting lipids: Total cholesterol, HDL-C, LDL-C, Triglycerides, VLDL-C, non-HDL-C,  
c Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Total protein, Albumin, Calcium, Magnesium, Phosphorus, Fasting Glucose, BUN or Urea, Creatinine, 
Uric acid, Total bilirubin, Direct bilirubin, CK, Alk phos, LDH, AST (SGOT), ALT (SGPT) 
d Hematology: RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, WBC, Platelets 
e Urinalysis: Specific gravity, pH, Blood, Protein, Glucose, Bilirubin, WBC, RBC, Epithelial cells, Bacteria, Casts, Crystals 
f Subjects on Q2W dosing will continue non-clinic setting injections after the Week 12 visit per dosing regimen 
g Prior to on-site SC IP administration, women subjects of childbearing potential should have urine pregnancy test performed 
h Subjects on QM dosing will continue non-clinic setting injections after the Week 12 visit per dosing regimen 
With: 
a Review for adverse events, serious adverse events, and adverse device effects.  Adverse events possibly related to study procedures, adverse 
device effects, and serious adverse events are collected during the screening period from signing of the ICF through 30 days post last dose of IP or 
EOS, whichever is later. 
b Fasting lipids: Total cholesterol, HDL-C, LDL-C, Triglycerides, VLDL-C, non-HDL-C. 
c Chemistry: Sodium, Potassium, Chloride, Bicarbonate, Total protein, Albumin, Calcium, Magnesium, Phosphorus, Fasting Glucose, BUN or Urea, Creatinine, 
Uric acid, Total bilirubin, Direct bilirubin, CK, Alk phos, LDH, AST (SGOT), ALT (SGPT) . 
d Hematology: RBC, Hemoglobin, Hematocrit, MCV, MCH, MCHC, RDW, WBC, Platelets. 
e Prior to on-site SC IP administration, female subjects of childbearing potential should have urine pregnancy test performed. 
f Urinalysis: Specific gravity, pH, Blood, Protein, Glucose, Bilirubin, WBC, RBC, Epithelial cells, Bacteria, Casts, Crystals. 
g Subjects on Q2W dosing will continue non-clinic setting injections after the Week 12 visit per dosing regimen. 
h Subjects on QM dosing will continue non-clinic setting injections after the Week 12 visit per dosing regimen. 
i For Q2W subjects only. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 17 of 30 
Section:  7.2 General Study Procedures, Analyte Listing Table, Footnote* 
Replace: 
HCV antibodies are measured before initiating treatment with investigational product in 
subjects at high risk for HCV infection and in subjects with ALT or AST > 2x ULN at any 
time during screening.  Please note that subjects with ALT or AST > 2x ULN must be 
screen failed unless the elevation is transient as confirmed by retesting.  High risk 
subjects for this protocol are those who meet any of the following conditions: 
With: 
HCV antibodies are measured before initiating treatment with investigational product in 
subjects at high risk for HCV infection and in subjects with ALT or AST > 2x ULN at any 
time during screening.  Conditions that may place subjects at high risk for HCV 
infection include the following: 
Section:  7.2 General Study Procedures, Paragraph 4 
Delete: 
Some laboratory results may inadvertently unblind investigators to treatment assignment 
to evolocumab.  Central laboratory results of the lipid panel, ApoA1, ApoB, Lp(a), 
Vitamin E and hsCRP posttreatment to week 24 will not be reported to the investigator 
until the unblinding of the clinical database. 
Section:  7.2.2 Screening Enrollment and/or Randomization, Paragraph 1, Bullet 4 
Replace: 
• 
Review for Adverse Events, Serious Adverse Events (only AEs possibly related to 
study procedures and SAEs are collected during the screening period from signing of 
informed consent [ICF]), Adverse Device Effects, and CV Events 
With: 
• 
Review for adverse events, serious adverse events, and adverse device effects.  
Adverse events possibly related to study procedures, adverse device effects, and 
serious adverse events are collected during the screening period from signing of 
the ICF 
Section:  7.2.2 Screening Enrollment and/or Randomization, Paragraph 1, Bullets 10-12 
Add: 
• 
Central Laboratory Assessments (as per Schedule of Assessments): 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 18 of 30 
• 
Subject instruction on self-administration of evolocumab for AI/Pen or 
Personal Injector 
• 
AI/Pen placebo injection (does not need to be repeated for rescreening) 
Section:  7.2.2 Screening Enrollment and/or Randomization, Paragraph 1, Bullet 10, 
Sub-bullet 1 
Delete: 
• 
Blood draw for fasting lipids (≥ 9 hour fasting sample), chemistry (including fasting 
glucose), CK, hematology, HbA1c, TSH, (Note: eGFR will be calculated by the 
central laboratory and will be provided to the site for eligibility determination), blood 
draws for hepatitis C virus (HCV) antibodies in subjects at high risk for, or with 
history of, HCV infection and in subjects with AST or ALT > 2x ULN at any time 
during screening, HCV viral load (only in subjects positive for HCV), serum FSH 
(only if required to ensure menopause in a female subject by central laboratory) 
Section:  7.2.3.1 Visit Day 1 (Randomization), first sentence 
Delete: 
The following procedures should be conducted at this visit for all subjects unless 
specified otherwise (± 3 days). 
Section:  7.2.3.1 Visit Day 1 (Randomization), Paragraph 1, Bullet 6 
Replace: 
• 
Urine pregnancy test (for women subjects of childbearing potential only) 
With: 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  precedes 
on-site SC IP administration 
Section:  7.2.3.1 Visit Day 1 (Randomization), Paragraph 1, Bullet 11 
Replace: 
• 
AI/Pen or Personal Injector subject instruction on self-administration of evolocumab 
With: 
• 
Subject instruction on self-administration of evolocumab for AI/Pen or 
Personal Injector 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 19 of 30 
Section:  7.2.3.2 Visit/Week 2, Paragraph 1, Bullet 5 
Add: 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
Section:  7.2.3.2 Visit/Week 2, Paragraph 1, Bullet 8 
Replace: 
• 
AI/Pen or Personal Injector subject instruction on self-administration of evolocumab 
With: 
• 
Subject instruction on self-administration of evolocumab for AI/Pen or 
Personal Injector 
Section:  7.2.3.5 Visit/Week 8, Paragraph 1, Bullet 6 
Add: 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
Section:  7.2.3.6 Visit/Week 10, Paragraph 1, Bullet 6 
Add: 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration 
Section:  7.2.3.6 Visit/Week 10, Paragraph 1, Bullet 10 
Add: 
• 
PO IP dispensing 
Section:  7.2.3.7 Visit/Week 12, Paragraph 1, Bullet 8 
Add: 
• 
Urine pregnancy test (for female subjects of childbearing potential only):  
precedes on-site SC IP administration visits 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 20 of 30 
Section:  7.2.4 Safety Follow-up / End of Study Phone Call/Week 54 (± 3 days), heading 
Add: 
7.2.4 Safety Follow-up / End of Study Phone Call/Week 54 (± 3 days) 
Section:  9.1.1 Definition of Adverse Events, Paragraph 4 
Add: 
An adverse device effect is any adverse event related to the use of a combination 
product or a medical device. 
Section:  9.1.2 Definition of Serious Adverse Events, Paragraph 3 
Add: 
Examples of such events could include allergic bronchospasm, convulsions, blood 
dyscrasias, DILI (see Appendix A for drug-induced liver injury reporting criteria), or 
events that necessitate an emergency room visit, outpatient surgery, or urgent 
intervention. 
Section:  9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria, Paragraph 1 
Replace: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment and all adverse events 
possibly related to study procedures from signing of the informed consent through the 
safety follow-up/end of study (End of Study Phone Call) are reported using the 
applicable eCRF (eg, Adverse Event Summary). 
With: 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment and all adverse events 
possibly related to study procedures and all adverse device effects from signing of the 
informed consent through the safety follow-up/end of study (End of Study Phone Call) 
are reported using the applicable eCRF (eg, Event eCRF). 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 21 of 30 
Section:  9.2.1 Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria, Paragraph 3 
Add: 
Is there a reasonable possibility that the event may have been caused by SC IP or PO 
IP?  Relatedness means that there are facts or reasons to support a relationship 
between IP and the event. 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events, Paragraph 3 
Add: 
Is there a reasonable possibility that the event may have been caused by SC IP or PO 
IP?  Relatedness means that there are facts or reasons to support a relationship 
between IP and the event. 
Section:  9.2.2 Reporting Procedures for Serious Adverse Events, Paragraph 7 
Delete: 
Information provided about the serious adverse event must be consistent with that 
recorded on the applicable eCRF (eg, Adverse Event Summary eCRF) 
Section:  9.2.3 Reporting Serious Adverse Events After the Protocol-required Reporting 
Period, (Moved from Section 9.2.2, Paragraph 2) 
Add: 
9.2.3 Reporting Serious Adverse Events After the Protocol-required Reporting 
Period 
After the protocol-required reporting period defined above or after end of study, the 
investigator does not need to actively monitor subjects for serious adverse events.  
However, if the investigator becomes aware of a serious adverse event after this 
protocol required reporting period or after end of study, the investigator will report the 
event to Amgen within 24 hours following the investigator’s knowledge of the event. 
Serious adverse events reported outside of the protocol-required reporting period or 
after end of study will be captured within the safety database as clinical trial cases for 
the purposes of expedited reporting. 
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 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 22 of 30 
EDC has been taken off-line, then the site can report this information on a paper 
Serious Adverse Event Report Form (eSAE Contingency Report Form). 
Section:  9.3 Pregnancy and Lactation Reporting, Paragraph 1 
Replace: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking protocol-required therapies report the pregnancy to Amgen as specified 
below. 
With: 
If a pregnancy occurs in a female subject, or female partner of a male subject, while the 
subject is taking evolocumab report the pregnancy to Amgen as specified below. 
Section:  9.3 Pregnancy and Lactation Reporting, Paragraph 3 
Replace: 
The pregnancy should be reported to Amgen’s global Pregnancy Surveillance Program 
within 24 hours of the investigator’s knowledge of the event of a pregnancy.  Report a 
pregnancy on the Pregnancy Notification Worksheet (Appendix C).  The Pregnancy 
Surveillance Program (PSP) will seek to follow the pregnant woman throughout her 
pregnancy and her baby up to 12 months after birth. 
With: 
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be 
requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events. 
Section:  9.3 Pregnancy and Lactation Reporting, Paragraph 6 
Replace: 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of protocol-required therapies through an 
additional 15 weeks after the end of treatment with IP, report the lactation case to 
Amgen, as specified below. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 23 of 30 
With: 
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur after the last dose of evolocumab through an additional 
15 weeks after the end of treatment with evolocumab, report the lactation case to 
Amgen, as specified below. 
Section:  9.3 Pregnancy and Lactation Reporting, Paragraph 7 
Replace: 
Any lactation case should be reported to Amgen’s global Lactation Surveillance Program 
(LSP) within 24 hours of the investigator’s knowledge of event.  Report a lactation case 
on the Lactation Notification Worksheet (Appendix C). 
With: 
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up 
with the investigator regarding additional information that may be requested. 
If a male subject's female partner becomes pregnant, the investigator should 
discuss obtaining information regarding the birth outcome and health of the infant 
from the pregnant partner. 
Section:  10.1.1 Study Endpoints, Exploratory Endpoints, Bullet 1 
Delete: 
• 
Subject incidence of adjudicated events: 
o Death by any cause 
o Cardiovascular death 
o Myocardial infarction 
o Hospitalization for unstable angina 
o Coronary revascularization 
o Stroke 
o Hospitalization for heart failure 
o Transient ischemic attack (TIA) 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 24 of 30 
Section:  10.4.2 Primary Analysis 
Replace: 
To evaluate efficacy and safety of 12 weeks of evolocumab compared with ezetimibe, 
the primary analysis will be performed when all the randomized subjects in the study 
have either completed the scheduled visits up to and including Week 12 or have early 
terminated from the study. At that time, the database of the study will be cleaned, 
processed and a snapshot will be taken; the study will also be unblinded. 
With: 
To evaluate efficacy and safety of 12 weeks of evolocumab compared with ezetimibe 
and summarize 12 weeks of data from the open-label extension (weeks 12 to 24), 
the primary analysis will be performed when all the randomized subjects in the study 
have either completed the scheduled visits up to and including Week 24 or have early 
terminated from the study. At that time, the database of the study will be cleaned, 
processed and a snapshot will be taken; the study will also be unblinded. 
Section:  10.5.1 General Considerations, Paragraph 1 
Replace: 
The superiority of evolocumab to ezetimibe will be assessed for all efficacy endpoints. 
With: 
The treatment effect of evolocumab compared to ezetimibe will be evaluated for all 
efficacy endpoints through the Week 12 visit.  In addition, descriptive analyses from 
the open-label extension (weeks 12 to 24) will be performed on OLEAS. 
Section:  10.5.2 Primary Efficacy Endpoint, Additional Analyses 
Add: 
The co-primary endpoints will also be assessed within each dose frequency using dose 
frequency matched control (ie, evolocumab Q2W SC plus placebo PO QD vs. ezetimibe 
QD plus placebo Q2W SC; evolocumab QM SC plus placebo PO QD vs. ezetimibe QD 
plus placebo QM SC) and pooled ezetimibe (ie, evolocumab Q2W vs. pooled ezetimibe; 
evolocumab QM vs. pooled ezetimibe). 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 25 of 30 
Section:  10.5.5 Safety Endpoints, After Paragraph 1 
Delete: 
Subject incidence of all disease related events and fatal disease related events will be 
tabulated by system organ class and preferred term. 
Section:  10.5.6 Exploratory Endpoint Analyses, Paragraph 2 
Delete: 
Death, myocardial infarction, hospitalization for unstable angina, coronary 
revascularization, stroke, TIA, and hospitalization for heart failure will be adjudicated by 
an independent CEC.Non-coronary revascularizations will be collected on the eCRF and 
will not be adjudicated.  Subject incidence of exploratory endpoint events will be 
summarized for each treatment group. 
Section:  12.6 Publication Policy, Paragraph 2 and bullet 1 
Replace: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published.  Authors should meet conditions 1, 2, and 3. 
With: 
Authorship of any publications resulting from this study will be determined on the basis 
of the Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (International Committee of Medical Journal 
Editors, 2013, updated 2014), which states: 
• 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the 
work in ensuring that questions related to the accuracy or integrity of any part 
of the work are appropriately investigated and resolved.  Authors should meet 
conditions 1, 2, 3, and 4. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 26 of 30 
Section:  Appendix A, Drug-induced Liver Injury Reporting & Additional Assessments 
Reporting, Paragraph 1 Bullet 2 
Delete: 
• 
The appropriate eCRF (eg, Adverse Event eCRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to the Amgen. 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 27 of 30 
Section:  Appendix C 
Replace: 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 28 of 30 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 29 of 30 
With: 
 
CONFIDENTIAL 
 


Product:  Evolocumab 
Protocol Number:  20140234 
Date:  21 March 2017 
Page 30 of 30 
 
CONFIDENTIAL 
 


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Amgen Protocol Number (Evolocumab) 20140234

Original Protocol:
20 January 2015
Amendment Date:
09 September 2015
5DWLRQDOH
The protocol is being amended for the following key reasons: 
x 
To reduce the washout period for ezetimibe from 4 weeks to 1 week. In the initial 
protocol, a 4-week washout for ezetimibe was mandated in order to remain 
consistent with the other evolocumab protocols.  Since ezetimibe half-life is 22 hours, 
a 1-week washout is sufficient to ensure adequate washout for accurate baseline 
lipid laboratories.  Based on updated feedback from Japanese opinion leaders, the 
standard 4-week ezetimibe washout was expected to create a large hurdle for 
enrollment therefore reducing the washout time to 1-week is necessary.
x
To reduce the approximate sample size from 100 to 60 subjects.  In the initial 
protocol, a sample size of 100 subjects was selected because it provided a 
conservative number of subjects to evaluate safety in a high risk population.  Based 
on feasibility results, it appears very unlikely that 100 subjects can be enrolled in a 
reasonable timeframe.  Based on updated feedback from Japanese opinion leaders, 
a sample size of 60 is considered feasible and adequate to assess safety in this 
patient population. Study power has also been updated to reflect the change in 
sample size.
x
Remove PO IP dispensing from week 10 as week 8 dispensing provides a sufficient 
supply of IP. 
x
Correct IP dispensation/accountability in schedule of events. 
x
Revise study schema to include all on-site visits. 
x
Revise exclusion criteria with updated contraception language. 
x
Clarify adverse event collection language and clarify adverse event definition. 
x
Add “Adverse Device Effects” review at each visit as per new protocol template.


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x
Add footnote to schedule of events on collection of SAEs to maintain consistency 
within the protocol. 
x
Add IP PO dispensation/accountability to schedule of events to maintain consistency 
within the protocol. 
x
Add SC IP accountability to study procedures at week 52 to maintain consistency 
with schedule of events.
x
Additional additions and clarifications added throughout after PMDA review, 
including:
x
Addition of “GAUSS-4:  Goal Achievement after Utilizing an anti-PCSK9 antibody 
in Statin Intolerant Subjects” to end of protocol title
x
Clarified laboratory results will remain blinded from posttreatment to week 24
until unblinding of the clinical database.
x
Clarified investigators will be provided laboratory results starting with week 24
until the end of study
x
Removed pharmacogenetic analysis from protocol
x
Changed number of sites from approximately 20 to approximately 40
x
Make minor corrections and clarifications throughout, including administrative, 
typographical, and formatting changes.

SAP_001.pdf: 
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33'
NCT Number: 2634580 
This NCT number has been applied to the document  
for purposes of posting on clinicaltrials.gov


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Product:  Evolocumab 
Statistical Analysis Plan:  20140234 
Date:  16 May 2018 
Page 25 
 
Table 3.  Key Efficacy Analyses Summary 
Endpoint 
Statistical 
Analysis 
Method 
P-values from the 
Statistical Tests 
Hierarchical 
Testing Procedure 
as Specified in the 
Multiplicity 
Adjustment Method 
Diagram 
Testing of Pooled 
EvomabTreatment 
Effect vs. Ezetimibe 
Co-Primary Endpoints 
 
 
Mean percent change from 
baseline at weeks 10 and 
12 in LDL-C 
 
Percent change from 
baseline at week 12 in 
LDL-C 
Repeated 
measures model  
P1 = Maximum of the two 
p-values for the 
co-endpoint pair from the 
primary analysis in FAS 
P1 compare to  
 = 0.05 
Co-Secondary Endpoints  
(Tier 1) 
 
 
Mean LDL response 
(achievement of LDL-C 
< 70 mg/dL) at weeks 10 
and 12  
 
LDL response at week 12  
Cochran 
Mantel-Haenszel 
(CMH) test 
P2a = Maximum of the 
two p-values for the 
co-endpoint pair in FAS 
If P1 < 0.05, 
 P2a and all 
P2b’s will be 
tested through 
Hochberg 
method with 
  =  0.005 
Else (ie, co-primary 
endpoint in FAS is 
not significant) 
 No further 
testing. 
 
Mean change from baseline 
at weeks 10 and 12 in 
LDL-C 
 
Change from baseline at 
week 12 in LDL-C 
and 
 
Mean percent change from 
baseline at weeks 10 and 
12  
 
Percent change from 
baseline at week 12  
in each of the following lipid 
parameter: 
total cholesterol, 
non-HDL-C, ApoB, total 
cholesterol/HDL-C ratio, 
ApoB/ApoA1 ratio 
Repeated 
measures model 
For each lipid parameter, 
 
P2b = Maximum of the 
two p-values for each  
co-endpoint pair in FAS 
 
 
Co-Secondary Endpoints 
 (Tier 2) 
 
 
Mean percent change from 
baseline at weeks 10 and 
12 
 
Percent change from 
baseline at week 12  
in each of the following lipid 
parameters: 
Lp(a), triglycerides, HDL-C, 
and VLDL-C 
Repeated 
measures model 
For each lipid parameter, 
 
P2c = Union-intersection 
test p-value from the two 
contrasts of each 
co-endpoint pair in FAS 
 
If P2a and all P2b’s 
are significant 
through Hochberg 
method,  
 P2c will be 
tested through 
Hochberg 
method with 
  =  0.05. 
Else (ie, not all tier 1 
co- endpoints in FAS 
are significant),  
 P2c will be 
tested through 
Hochberg 
method with 
  =  0.045.


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Product:  Evolocumab 
Statistical Analysis Plan:  20140234 
Date:  16 May 2018 
Page 32 
 
Appendix A.  Framingham Risk Score (FRS) 
Method to calculate the Framingham Risk Score (FRS): 
The β coefficients given in the two tables below are used to compute a linear function.  
The latter is corrected for the averages of the participants’ risk factors (mean) from the 
Framingham study, and the subsequent result is exponentiated and used to calculate a 
10-year probability of HCHD after insertion into a survival function (Wilson et al). 
The calculation is different for men and women and use the following coefficients βi, 
where i represents each of the independent variables.  The values below are from the 
Framingham heart study (http://www.framinghamheartstudy.org/risk-functions/ 
coronary-heart-disease/hard-10-year-risk.php).   
t_chol = total cholesterol, hdl = HDL-C, sbp = systolic blood pressure, trt_htn = treatment 
for hypertension (if sbp > 120), smoker = current smoker 
Men 
 
 
 
 
 
 
 
 
 
 
 
 
 
Women 
Independent 
variable 
Coefficient 
βi 
mean 
Independent 
variable 
Coefficient 
βi 
mean 
ln(age) 
52.00961
3.8926095
ln(age) 
31.764001 
3.9213204
ln(t_chol) 
20.014077
5.3441475
ln(t_chol) 
22.465206 
5.3628984
ln(hdl) 
-0.905964
3.7731132
ln(hdl) 
-1.187731 
4.0146369
ln(sbp) 
1.305784
4.8618212
ln(sbp) 
2.552905 
4.8376494
trt_htn 
(spb>120) 
0.241549
0.1180474
trt_htn 
(spb>120) 
0.420251 
0.142802
smoker 
12.096316
0.335602
smoker 
13.07543 
0.3236202
ln(age)* 
ln(t_chol) 
-4.605038
20.8111562
ln(age)* 
ln(t_chol) 
-5.060998 
21.0557746
ln(age)*smoker1 
-2.84367
1.2890301
ln(age)*smoker2 
-2.996945 
1.2519882
ln(age)*ln(age) 
-2.93323
15.2144965
 
 
1 if age>70 then ln(70)*smoker 
2 if age>78 then ln(78)*smoker 
The steps to determine the FRS is the same for men and women. 
Men 
For each subject: 
1. Calculate Lmen = βln(age)*ln(age) + βln(t_chol)*ln(t_chol) + βln(hdl) *ln(hdl) + 
βln(sbp)*ln(sbp) + βtrt_htn*(if trt_htn) + βsmoker*(if smoker) + β 
ln(age)*ln(t_chol)*ln(age)*ln(t_chol) + βln(age)*smoker*ln(age)*(if smoker)  + 
βln(age)*ln(age)*ln(age)*ln(age) 
2. Calculate Amen = Lmen - 172.300168 (note: the value of 172.300168 was derived 
based on the mean columns in above table) 
3. Calculate Bmen = exp (Amen) 


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Product:  Evolocumab 
Statistical Analysis Plan:  20140234 
Date:  16 May 2018 
Page 35 
 
Scheduled Visit 
Week 
Week 2 
Week 8 
Week 10 
Week 12 
Week 24 
Week 36 
Week 48 
Week 52 
Week 54 
EOS Phone 
Call 
Scheduled Visit Day 
15 
57 
71 
85 
169 
253 
337 
365 
379 
Vital Signs 
 
(1, 63] 
(63, 77] 
(77, min(91, first 
dose date of OLE)] 
(min(91, first dose 
date of OLE), 210] 
(210,294] 
(294,350] 
>350 
 
Fasting Lipids 
(1, 35] 
(35, 63] 
(63, 77] 
(77, min(91, first 
dose date of OLE)] 
(min(91, first dose 
date of OLE), 210] 
(210,294] 
(294,350] 
(350,378] 
 
Lp(a), ApoA1, ApoB 
 
 
(1, 77] 
(77, min(91, first 
dose date of OLE)] 
(min(91, first dose 
date of OLE), 210] 
(210,294] 
(294,350] 
(350,378] 
 
PK, PCSK9 
(1, 42] 
 
(42, 77] 
(77, min(91, first 
dose date of OLE)] 
 
 
 
(min(91, first 
dose date of 
OLE), 378] 
 
Hematology and 
Chemistry 
 
(1, 70] 
 
(70, min(91, first 
dose date of OLE)] 
 
 
 
> min(91, first 
dose date of 
OLE) 
 
Physical Exam, 
hsCRP, Urinalysis, 
HbA1c, Biomarkers, 
anti-evolocumab 
antibodies 
 
 
 
(1, min(91, first 
dose date of OLE)] 
 
 
 
> min(91, first 
dose date of 
OLE) 
 
Weight, waist 
circumference 
 
 
 
 
 
 
 
> 1 
 


Product:  Evolocumab 
Statistical Analysis Plan:  20140234 
Date:  16 May 2018 
Page 36 
 
Handling multiple records assigned to an analytical study week: 
If there is more than one record in a study week interval, the analytical record for that 
specific study week will be defined as the record closest to the scheduled visit day of 
that specific study week (7 x study week + 1).  If two records are equidistant from the 
scheduled day, then the earlier record will be chosen.  If there are multiple records on 
the same day, the last record will be used. 


Product:  Evolocumab 
Statistical Analysis Plan:  20140234 
Date:  16 May 2018 
Page 37 
 
Appendix C.  Common Terminology Criteria for AEs (CTCAE) 
Refer to the NCI Common Terminology Criteria for AEs (CTCAE) for AEs and lab shift 
grading and information.  The CTCAE is available at the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html