Clinical trial NCT04987320
Conditions: Elevated Serum Lipoprotein(a)
Keywords: Elevated serum lipoprotein(a) Olpasiran
Sponsor: Amgen
Start date: 2021-07-28; Completion date: 2022-03-18
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of this study is to evaluate the pharmacokinetics (PK) of a single dose of Olpasiran in Chinese participants with elevated serum lipoprotein(a) (Lp\[a\]).

Detailed description:

Arms: arm 1: Participants will be administered Olpasiran dose A as a subcutaneous injection. arm 2: Participants will be administered Olpasiran dose B as a subcutaneous injection.
Interventions: intervention 1: Olpasiran
Intervention descriptions: intervention 1: Subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Protocol 
CONFIDENTIAL 
Labcorp Study: 8424665AMGEN Protocol Reference: 20190095 
Protocol Version 3.0, 28 July 2021 Page 1 of 79 
Protocol 
An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety and Tolerability of Olpasiran in Chinese Subjects With 
Elevated Serum Lipoprotein(a) 
Protocol Status: Final 
Protocol Date: 28 July 2021 
Protocol Version: 3.0 
Investigational Product: Olpasiran (AMG 890) 
Amgen Protocol Reference Number: 20190095 
Labcorp Study Number: 8424665 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
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NCT Number: NCT04987320
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


Protocol 
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Labcorp Study: 8424665AMGEN Protocol Reference: 20190095 
Protocol Version 3.0, 28 July 2021 Page 2 of 79 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the Institutional Review Board/Independent Ethics Committee/Institutional 
Scientific Review Board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number: US sites, 1-800-77-AMGEN; Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US, 1-805-447-1000. 
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Protocol 
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Labcorp Study: 8424665AMGEN Protocol Reference: 20190095 
INVESTIGATOR AGREEMENT 
I have read the protocol entitled MAn Open-label, Single-dose Study to Evaluate the 
Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Olpasiran in Chinese Subjects 
with Elevated Serum llpoprotein(a}" and agree to conduct the study as described herein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite Guideline on 
Good Clinical Practice (GCP), Declaration of Helsinki, and applicable national or regional 
regulations/guidelines. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Amgen Inc. 
Signature 
 
Name of Investigator 
Date (DD Month 2021} 
Protocol Version 3.0, 28 July 2021 Page 3 of 79 
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STUDY IDENTIFICATION 
Sponsor 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Sponsor’s Study Contact 
, Ph.D.  
Director, Clinical Pharmacology 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Tel:
 
Email:
Medical Monitor 
, M.D., Ph.D. 
Medical director 
Labcorp, Inc.  
3301 Kinsman Boulevard  
Madison, Wisconsin 53704  
USA  
Tel: 
 
Email:
Sponsor’s Study Manager 
 
Global Early Clinical Development Manager 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Tel: 
  
Email:
Labcorp Project Manager 
  
Senior Project Manager 
Labcorp Clinical Pharmacology Services 
USA 
Tel: 
Email:
Statistician 
, M.S. 
Labcorp, Inc. 
3301 Kinsman Boulevard 
Madison, Wisconsin 53704 
USA 
Tel: 
  
Email:
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SYNOPSIS 
Title of study: An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety and Tolerability of Olpasiran in Chinese Subjects with Elevated 
Serum Lipoprotein(a) 
Objectives:  
The primary objective of the study is: 
 
to evaluate the pharmacokinetics (PK) of a single dose of Olpasiran in Chinese 
subjects with elevated serum lipoprotein(a) (Lp[a]).  
The secondary objectives of the study are: 
 
to evaluate the safety and tolerability of a single dose of Olpasiran in Chinese subjects 
with elevated serum Lp(a)  
 
to evaluate the pharmacodynamics (PD) of a single dose of Olpasiran in Chinese 
subjects with elevated serum Lp(a). 
Study design: 
This will be an open-label, randomized, single-dose parallel group study in Chinese subjects 
with elevated serum Lp(a). Potential subjects will be screened within 40 days prior to the dose. 
Subjects will be admitted into the phase I Clinical Research Unit (CRU) on Day -1 and will be 
confined to the CRU until discharge on Day 4. Subjects will return to the CRU for out-patient 
visits on Days 7, 15, 29, 57, 85, 113, 155, and 183, and at the End of Study (EOS) visit on Day 
225. A telephone visit will be scheduled for treatment emergent adverse event (TEAE) 
assessments on Day 211. Subjects will be randomized in a 1:1 ratio to receive a single 
subcutaneous (SC) dose of Olpasiran at 
 mg (Group A) or 
 mg (Group B). 
Number of subjects: 
Approximately 24 subjects (12 per group) will be enrolled in the study.   
Diagnosis and main criteria for inclusion: 
Male or female subjects living in mainland China, Hong Kong, or Taiwan, and of Chinese 
ancestry, 18 to 60 years of age (inclusive), body mass index of 18 to 32 kg/m2 (inclusive), and 
serum Lp(a)  70 nmol/L (or approximately  27 mg/dL). 
Investigational products, dose, and mode of administration: 
Investigational Medicinal Product: 
 mg/mL Olpasiran. 
Group A  
 mg administered as a 
 (
 mg/mL) SC injection 
Group B  
 mg administered as 
 (
 mg/mL) SC injections 
Duration of subject participation in the study: 
Planned Screening duration: approximately 6 weeks. 
Planned study duration (Screening to EOS): approximately 38 weeks.  
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Endpoints: 
Primary: 
The primary endpoints for this study are Olpasiran PK parameters: 
 
maximum observed concentration (Cmax) 
 
area under the concentration-time curve (AUC) 
Additional PK parameters may include, but are not limited to: time to maximum observed 
concentration (tmax), half-life (t1/2), apparent volume of distribution during the terminal 
elimination phase (Vz/F), and apparent total body clearance (CL/F).  
Secondary: 
Secondary endpoints for this study are: TEAEs, clinical laboratory tests, 12-lead 
electrocardiograms (ECGs), vital signs, lipids and serum Lp(a).  
Statistical methods: 
Data will be analyzed for all subjects who are randomized and receive Olpasiran. Descriptive 
statistics by treatment group will be provided for selected demographics, safety, PK and Lp(a) 
data. Descriptive statistics on continuous measurements will include means, medians, 
standard deviations, and ranges, while categorical data will be summarized using frequency 
counts and percentages. PK, Lp(a), lipids, vital signs, electrocardiogram, and clinical 
laboratory data will be summarized at each scheduled visit per Schedule of Assessment.  
The final safety analysis for the study will be performed at the end of the study. Each TEAE will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA). No imputation will 
be done for safety assessments and endpoints for clinical laboratory tests, 12-lead ECGs, and 
vital signs will be summarized using descriptive statistics. 
Additional details will be included in the Statistical Analysis Plan. 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ................................................................................................ 3 
STUDY IDENTIFICATION......................................................................................................... 4 
SYNOPSIS ............................................................................................................................... 5 
TABLE OF CONTENTS ............................................................................................................ 7 
LIST OF TABLES AND FIGURES ........................................................................................... 10 
LIST OF ABBREVIATIONS ..................................................................................................... 11 
1. 
INTRODUCTION ............................................................................................................ 13 
1.1 
Background ........................................................................................................ 13 
1.2 
Nonclinical Summary .......................................................................................... 14 
1.2.1 
Pharmacology ..................................................................................... 14 
1.2.2 
Pharmacokinetic ................................................................................. 14 
1.2.3 
Toxicology ........................................................................................... 15 
1.3 
Clinical Summary ................................................................................................ 17 
1.4 
Study Rationale .................................................................................................. 19 
1.5 
Benefit-risk Assessment ..................................................................................... 19 
1.5.1 
Key Benefits ........................................................................................ 19 
1.5.2 
Risks ................................................................................................... 20 
2. 
OBJECTIVES AND ENDPOINTS ................................................................................... 21 
2.1 
Objectives ........................................................................................................... 21 
2.2 
Endpoints ........................................................................................................... 21 
2.2.1 
Primary Endpoints ............................................................................... 21 
2.2.2 
Secondary Endpoints .......................................................................... 21 
3. 
INVESTIGATIONAL PLAN ............................................................................................. 23 
3.1 
Overall Study Design and Plan ........................................................................... 23 
3.2 
Discussion of Study Design ................................................................................ 24 
3.3 
Selection of Doses in the Study .......................................................................... 24 
3.4 
End of Study ....................................................................................................... 25 
4. 
SELECTION OF STUDY POPULATION ........................................................................ 26 
4.1 
Inclusion Criteria ................................................................................................. 26 
4.2 
Exclusion Criteria ................................................................................................ 27 
4.3 
Screen Failures and Rescreening ....................................................................... 29 
4.4 
Subject Number and Identification ...................................................................... 29 
4.5 
Subject Withdrawal and Replacement ................................................................ 30 
4.6 
Study Termination............................................................................................... 30 
5. 
STUDY TREATMENTS .................................................................................................. 31 
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5.1 
Investigational Product ....................................................................................... 31 
5.2 
Treatment of Overdose ....................................................................................... 32 
5.3 
Randomization .................................................................................................... 32 
5.4 
Blinding ............................................................................................................... 33 
5.5 
Treatment Compliance ....................................................................................... 33 
5.6 
Drug Accountability ............................................................................................. 33 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ...................................... 33 
6.1 
Concomitant Therapies ....................................................................................... 33 
6.2 
Diet ..................................................................................................................... 34 
6.3 
Exercise .............................................................................................................. 34 
6.4 
Blood Donation ................................................................................................... 34 
7. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................. 34 
7.1 
Study Procedures ............................................................................................... 35 
7.1.1 
Screening, Enrollment, and/or Randomization .................................... 35 
7.1.2 
Treatment Period ................................................................................ 36 
7.1.3 
End of Study ....................................................................................... 36 
7.2 
General Assessments ......................................................................................... 36 
7.2.1 
Informed Consent ............................................................................... 36 
7.2.2 
Demographics ..................................................................................... 36 
7.2.3 
Physical Examination .......................................................................... 36 
7.2.4 
Physical Measurements ...................................................................... 37 
7.2.5 
Medical History ................................................................................... 37 
7.3 
Pharmacokinetic Assessments ........................................................................... 37 
7.3.1 
Pharmacokinetic Blood Sample Collection and Processing ................. 37 
7.3.2 
Analytical Methodology ....................................................................... 37 
7.4 
Pharmacodynamic Assessments ........................................................................ 37 
7.4.1 
Pharmacodynamic Blood Sample Collection and Processing .............. 37 
7.4.2 
Analytical Methodology ....................................................................... 37 
7.5 
Anti-Olpasiran Antibody Assessments ................................................................ 38 
7.6 
Safety and Tolerability Assessments .................................................................. 38 
7.6.1 
Treatment-Emergent Adverse Events and Serious Treatment-Emergent 
Adverse Events: Time Period and Frequency for Collecting and 
Reporting Safety Event Information .................................................... 38 
7.6.2 
Clinical Laboratory Evaluations ........................................................... 41 
7.6.3 
12-Lead Electrocardiogram ................................................................. 42 
7.6.4 
Vital Signs ........................................................................................... 42 
8. 
SAMPLE SIZE AND DATA ANALYSIS........................................................................... 43 
8.1 
Determination of Sample Size ............................................................................ 43 
8.2 
Analysis Set ........................................................................................................ 43 
8.2.1 
Pharmacokinetic Analysis Set ............................................................. 43 
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8.2.2 
Pharmacodynamic Analysis Set .......................................................... 43 
8.2.3 
Safety Analysis Set ............................................................................. 43 
8.3 
Pharmacokinetic Analyses .................................................................................. 43 
8.4 
Pharmacodynamic Analyses ............................................................................... 44 
8.5 
Safety Analysis ................................................................................................... 44 
8.6 
Interim Analysis .................................................................................................. 44 
9. 
REFERENCES ............................................................................................................... 45 
10. 
APPENDICES ................................................................................................................ 47 
Appendix 1.  Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Treatment-emergent adverse event ........................ 48 
Appendix 2.  Clinical Laboratory Evaluations .................................................................. 57 
Appendix 3.  Approximate Total Blood Volume ............................................................... 59 
Appendix 4.  Contraception Requirements ..................................................................... 60 
Appendix 5.  Collection of Pregnancy and Lactation Information .................................... 62 
Appendix 6.  Regulatory, Ethical, and Study Oversight Considerations .......................... 66 
Appendix 7.  Hepatotoxicity: Suggested Actions and Follow-up Assessments................ 72 
Appendix 8.  Sample Storage and Destruction ............................................................... 75 
Appendix 9.  Schedule of Assessments.......................................................................... 76 
 
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LIST OF TABLES AND FIGURES 
Table 1.  Treatment Groups ................................................................................................... 23 
Table 2.  Investigational Product ............................................................................................ 32 
Table 3.  Safety Laboratory Evaluations ................................................................................. 57 
Table 4.  Pharmacodynamic Laboratory Evaluations ............................................................. 58 
Table 5.  Schedule of Assessments ....................................................................................... 76 
Table 6.  Schedule of Assessments ....................................................................................... 78 
 
Figure 1.  Study Schematic .................................................................................................... 23 
Figure 2.  Sample Serious Treatment-Emergent Adverse Event Report Form ....................... 53 
Figure 3.  Pregnancy Notification Form .................................................................................. 64 
Figure 4.  Lactation Notification Form ..................................................................................... 65 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
Apo B 
apolipoprotein B 
ApoA1 
apolipoprotein A1 
APTT 
activated partial thromboplastin time 
ASCVD 
atherosclerotic cardiovascular disease 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase 
AUC 
area under the serum concentration-time curve  
BP 
blood pressure 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CRU 
Clinical Research Unit 
CVD 
cardiovascular disease 
DILI 
drug-induced liver injury 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOS 
end of study 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
GalNac 
N-acetylgalactosamine 
HDL-C 
high-density lipoprotein cholesterol 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
IMP 
investigational medicinal product 
LDL-C 
low-density lipoprotein cholesterol 
Lp(a) 
lipoprotein(a) 
MDRD 
Modification of Diet in Renal Disease 
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Abbreviation 
Definition 
MI 
myocardial infarction 
NOAEL 
no observed adverse effect level 
PK 
pharmacokinetic(s) 
PD 
pharmacodynamics(s) 
PT 
prothrombin time 
QTcF 
QT interval corrected for heart rate based on the Fridericia correction 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
siRNA 
small interfering ribonucleic acid 
t1/2 
half-life 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
Tg 
transgenic 
tmax 
time to maximum observed concentration 
ULN 
upper limit of normal 
VLDL-C 
very low-density lipoprotein cholesterol 
Vz/F 
apparent volume of distribution during the terminal elimination phase 
 
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1. 
INTRODUCTION 
1.1 
Background 
According to the World Health Organization (WHO), cardiovascular disease (CVD) is the 
leading cause of death globally. An estimated 17.9 million people died from CVDs in 2016, 
representing 31 of all deaths worldwide1. Of the deaths related to CVD, approximately 85 
are from myocardial infarction (MI) and stroke1.  
The morbidity associated with MI and stroke continues to be serious and multifaceted, and 
reducing this morbidity is an important treatment goal. After a cardiovascular event, patients 
may struggle to regain their independence and suffer from both acute and long-term reductions 
in health-related quality of life, including diminished mobility and functionality, as well as 
increased anxiety, depression, fatigue, and sexual dysfunction2, 3, 4, 5, 6, 7. 
While lipid-lowering therapy research has historically focused on lowering low-density 
lipoprotein cholesterol (LDL-C) to reduce cardiovascular risk, elevated serum levels of 
lipoprotein(a) (Lp[a]) have recently been identified as a potential risk factor for atherosclerotic 
cardiovascular disease (ASCVD) 8, 9, 10, 11, 12. 
An Lp(a) molecule is composed of a LDL-like particle and an apo(a) that is bound to 
apolipoprotein B-100 by a disulfide bridge13. Lp(a) molecules are heterogeneous in size, 
depending upon the number of kringle IV type 2 repeats in the apo(a) gene14. Lp(a) levels are 
largely genetically determined, stable over time, and not significantly influenced by diet, 
exercise, or other environmental factors15. Lp(a) has been shown to have a pathogenic role in 
atherosclerosis and thrombosis formation16. The potential association between Lp(a) levels and 
coronary artery disease, MI, stroke, peripheral vascular disease, and aortic valve stenosis has 
been described in several genetic and observational studies13. 
Olpasiran (AMG 890) is a synthetic small interfering ribonucleic acid (siRNA) that targets the 
liver by conjugation to a tri-N-acetylgalactosamine moiety and inhibits the translation of apo(a) 
and Lp(a) production (the latter being a protein-lipid complex, of which apo[a] is a component). 
Olpasiran is being developed to reduce Lp(a) for the treatment of adults with ASCVD to reduce 
the risk of cardiovascular events. 
Amgen’s nonclinical program demonstrated that Olpasiran can achieve a sustained  80 
reduction in serum Lp(a) and is suitable for monthly subcutaneous (SC) administration. The 
studies supporting this conclusion included efficacy data collected from transgenic (Tg) mice 
and cynomolgus monkeys demonstrating that Lp(a) levels can be specifically targeted with 
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Olpasiran to inhibit apo(a) translation. Based on available data, Olpasiran is a potentially 
promising molecule to reduce Lp(a) for the treatment of adults with ASCVD to reduce the risk of 
cardiovascular events. Additional information related to the physical, chemical, and 
pharmaceutical properties and formulation(s), pharmacology and pharmacokinetic(s) (PK) of the 
Olpasiran is provided in the Investigator Brochure (IB)17.  
Currently, Olpasiran is being studied in two phase 1 studies in healthy subjects (first-in-human 
[FIH] Study 20170544 and Study 20180222). The FIH Study 20170544 is an ongoing double-
blind placebo-controlled study in healthy subjects with elevated plasma Lp(a), which is designed 
to evaluate safety and tolerability as primary endpoints, and to address PK and 
pharmacodynamics (PD) effects as secondary endpoints. Study 20180222 is a completed open-
label study in Japanese and non-Japanese subjects to characterize Olpasiran PK as the 
primary endpoint and assess safety and tolerability as the secondary endpoints. Olpasiran was 
evaluated at dose ranges of
mg to 
 mg in both phase 1 studies. 
1.2 
Nonclinical Summary 
A detailed description of the chemistry, pharmacology, and PK of Olpasiran is provided in the 
IB17.  
1.2.1 
Pharmacology 
The Olpasiran nonclinical pharmacology program to date has consisted of in vivo PD studies in 
Tg mice and cynomolgus monkeys and exploratory in vitro cytokine release and complement 
and platelet activation assays in human systems. In Tg mice, Olpasiran achieved  80 
reduction in serum Lp(a) for 36 days after administration of a single SC dose of 1 mg/kg. In 
cynomolgus monkeys, a single 2 mg/kg dose of Olpasiran significantly reduced serum Lp(a) and 
apo(a) levels by  80 for up to 6 weeks. In a dose response study in cynomolgus monkeys, 
Olpasiran demonstrated  80 reductions in serum Lp(a) in the 3 and 10 mg/kg dose groups.  
1.2.2 
Pharmacokinetic 
Olpasiran was administered subcutaneously (SC) to cynomolgus monkeys at a single dose of 
0.1, 1, 3, or 10 mg/kg. Olpasiran PK was linear over the dose range of 0.1 to 10 mg/kg SC. 
Mean terminal half-life (t1/2) values after SC administration ranged from 3.13 hours to 5.09 
hours. 
In repeat-dose toxicology studies in the cynomolgus monkey (see Section 1.2.3 below), 
Olpasiran exposure increased approximately in proportion to Olpasiran dose between 10 and 
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30 mg/kg and greater than dose proportionally between 30 and 150 mg/kg. No accumulation of 
Olpasiran was observed following multiple-dose administration. 
The in vitro metabolism of Olpasiran was evaluated in Sprague Dawley rats, cynomolgus 
monkeys, and human whole liver cell lysate preparations by high performance liquid 
chromatography-mass spectrometry (HPLC-MS). Metabolite profiles were qualitatively similar 
across species with no disproportionate human metabolites. Overall, the nonclinical PK and 
metabolism data support the clinical testing of Olpasiran in human subjects. 
1.2.3 
Toxicology 
The Sprague Dawley rat and cynomolgus monkey were selected as the species for nonclinical 
safety assessment. The SC route of administration was chosen based on the intended clinical 
route of administration. The monkey is a pharmacologic relevant animal model, in contrast to 
the rat, which does not produce apo(a). In monkey safety pharmacology assessments, there 
were no Olpasiran-related qualitative or quantitative electrocardiogram (ECG) changes or 
changes in blood pressure (BP), heart rate, body temperature, respiratory rate or neurological 
function at doses up to 150 mg/kg, the highest dose level tested. In the in vitro secondary PD 
studies, Olpasiran did not cause complement activation in human serum or cytokine stimulation 
or platelet activation in human whole blood. 
Olpasiran was well tolerated in the Investigational New Drug (IND)-enabling (57-day rat and 
monkey) and registrational (6-month rat, 9-month monkey) GLP toxicology studies.  All dose 
levels in the monkey toxicology studies reduced serum Lp(a) by  90.  In the IND-enabling 
GLP 57-day rat and monkey toxicology studies and in the registrational GLP 6-month rat and 9-
month monkey studies, Olpasiran was administered at 10, 30, and 150 mg/kg once monthly.  In 
rats at 10 mg/kg, the only Olpasiran related change was minimal to mild accumulation of 
basophilic granular material in the proximal convoluted tubular epithelium of the renal cortex in 
the 6-month study.  In monkeys at 10 mg/kg, the only Olpasiran-related changes were Kupffer 
cell hypertrophy/hyperplasia (with cytoplasmic vacuolization and basophilia) in the liver and 
vacuolation of macrophages in the subcutis at the injection site and in the lymph nodes; the 
vacuolation of macrophages in the subcutis at the injection site was not observed in the 9-month 
monkey toxicology study.  Olpasiran-related changes in the liver, kidneys, lymph nodes, and 
injection site were consistent with investigational product uptake, a known N-
acetylgalactosamine (GalNAc) conjugated siRNA-related platform effect and not specific to 
Olpasiran18, 19, 20. 
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There were other Olpasiran-related changes that occurred either at higher dose levels or a more 
frequent dosing regimen (e.g., weekly in the exploratory studies) included transient, minimal to 
mild increases in cholesterol (rats only), serum alanine aminotransferase (ALT), and minimal to 
mild increases in serum alkaline phosphatase (ALP), and bilirubin. Additional Olpasiran-related 
changes occurring at higher dose levels or with increased frequency of dosing included 
basophilic granules in the proximal tubular epithelial cells of the kidney. Olpasiran-related liver 
changes at higher dose levels or increased frequency of dosing consisted of hepatocellular 
vacuolation, increased single cell necrosis and mitoses of hepatocytes, and basophilic granular 
material in Kupffer cells in the liver in rats and hepatocellular hypertrophy with cytoplasmic 
rarefaction in monkeys. The only Olpasiran-related finding considered secondary to silencing of 
LPA gene expression was a reduction in serum Lp(a) in monkeys. None of the Olpasiran-related 
changes were considered adverse due to their low severity and absence of light microscopic 
evidence of tissue injury.  All the Olpasiran-related changes in rats were partially reversed at the 
end of the recovery phase in the 57-day study.  All the Olpasiran-related changes in monkeys 
were fully reversed at the end of the recovery phase in the 57-day study except for GalNAc 
conjugated siRNA platform related effects in Kupffer cells of the liver and mesenteric lymph 
node macrophages.  All the Olpasiran related changes in the 6-month rat toxicology study were 
partially or fully reversed at the end of a 4-month recovery period; the recovery period of the 9-
month monkey toxicology study is ongoing.  In both the rat and monkey, the no observed 
adverse effect level (NOAEL) for the GLP toxicology studies was determined to be 150 mg/kg, 
the highest dose evaluated. 
In an exploratory embryo fetal development toxicology study in the rat, there were no Olpasiran-
related mortalities, clinical signs, maternal ovarian or uterine abnormalities, or fetal external or 
visceral abnormalities when pregnant rats received up to 200 mg/kg Olpasiran SC daily on 
gestation Day (GD) 7 through GD 17.  In a GLP fertility and early embryonic development study 
in the rat, there were no Olpasiran-related clinical signs or macroscopic findings or effects on 
mating and fertility parameters, male reproductive organ weights, sperm parameters (vas 
deferens sperm motility, caudal epididymal sperm density, or sperm morphology) in males, and 
no Olpasiran-related clinical signs or macroscopic findings or effects on any ovarian or uterine 
parameter (corpora lutea, implantation sites, live and dead embryos), or on estrous cycling or 
mating and fertility in females.  Additionally, there were no Olpasiran-related microscopic effects 
observed in reproductive organs in the rat (up to 6-month duration) or monkey (up to 9-month 
duration) toxicology studies. 
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In conclusion, Olpasiran-associated changes were primarily associated with uptake of the 
siRNA molecule and were non-adverse. Based on the rat and monkey NOAEL from the GLP 
toxicology studies, there are sufficient safety margins for the doses studied in humans.  
1.3 
Clinical Summary 
Olpasiran is being studied in two phase 1 studies in healthy subjects, specifically a FIH Study 
20170544 and a Japanese PK Study 20180222. 
Study 20170544 (FIH) 
As of the 19 March 2020 data snapshot date, Olpasiran or placebo had been administered to 
64 subjects (48 Olpasiran and 16 placebo). Of these 30 subjects with screening plasma Lp(a) 
between  70 to  199 nmol/L received 5 different single doses (cohorts 1 to 5:
 
 mg) and 18 subjects with screening plasma Lp(a)  200 nmol/L received 2 different single 
doses (high Lp[a] cohorts 6 and 7: 
 mg). Two additional cohorts were added to Study 
20170544 and are ongoing (cohort 8 [
 mg] and cohort 9 [
 mg] included subjects with 
screening plasma Lp(a)  200 nmol/L). As of 19 March 2020, no data are available for reporting 
from cohorts 8 and 9. All 64 subjects enrolled in cohorts 1 to 7 of Study 20170544 have 
completed the treatment phase of the study (cohorts 1 and 2: Day 113 and cohorts 3 to 7: Day 
225). There have been no life-threatening or fatal adverse events (AEs) reported, and no 
serious AEs reported in subjects treated with Olpasiran. No clinically relevant changes in liver 
function tests, platelets or coagulation parameters, or renal function (creatinine) have been 
detected. Overall, no notable trends in AEs, vital signs, or laboratory results have been 
observed to date.  
After single doses of 
 mg, preliminary PK data in cohorts 1 to 7 indicated 
that Olpasiran was rapidly absorbed with maximum observed concentration (Cmax) occurring 
approximately 3 to 8 hours after dosing. The half-life (t1/2) ranged from 3 to 8 hours and 
Olpasiran was predominantly cleared from systemic circulation within 2 to 3 days. In general, 
serum exposures increased in an approximately dose-proportional manner at doses between  
 mg. Mean Olpasiran exposures in subjects with screening Lp(a)  200 nmol/L (cohorts 
6 and 7) were 53 to 55 and 18 to 33 lower compared to those in subjects with screening 
Lp(a)  70 to  199 nmol/L (cohorts 1 to 5) for Cmax and area under the concentration-time curve 
(AUC), respectively.  
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Study 20180222 (Japanese PK) 
Phase 1 Study 20180222 was conducted to evaluate the PK, safety, and tolerability of Olpasiran 
in Japanese and non-Japanese subjects; pre-study Lp(a) level was not an eligibility criterion. 
The study was an open-label, single SC dose study evaluating Olpasiran at 4 dose levels 
 
 mg; n  4 to 6 subjects per group). This study was designed to support integration 
of Japanese subjects (in Japan) into the global clinical phase 2 study. Eligible subjects received 
a single dose of Olpasiran by SC administration on Day 1 and PK samples were collected from 
predose through Day 29. Subjects were assessed for safety endpoints and for serum Lp(a) 
levels from screening through Day 225. 
Olpasiran was administered to a total of 27 subjects: 21 subjects in 4 different single doses (
 
 mg) in Japanese subjects and to 6 subjects in 1 single dose (
 mg) in non-
Japanese subjects. Olpasiran was shown to be safe and well tolerated. No patterns indicative of 
clinically important adverse events, laboratory abnormalities, or vital sign abnormalities were 
observed. No serious or fatal adverse events were reported from this study.  
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A detailed description of the efficacy and safety of Olpasiran is provided in the IB17.  
1.4 
Study Rationale 
This study will be conducted to confirm and evaluate the PK, PD, safety, and tolerability of a 
single dose of Olpasiran at two dose levels (
 mg and 
 mg) in Chinese subjects with 
elevated serum Lp(a) to support the conduct of further clinical studies of Olpasiran in mainland 
China, Hong Kong, or Taiwan. 
1.5 
Benefit-risk Assessment 
Despite the scientific advances of the last 50 years leading to an armamentarium of 
evidence-based guidelines and risk reducing drugs, ASCVD still represents a major cause of 
death and morbidity, and an enormous financial burden21. Recently, elevated serum Lp(a) has 
been identified as a strong independent risk factor for the development and progression of 
atherosclerotic disease15. Lp(a) has been associated with increased risk for MI, aortic valve 
stenosis development, carotid artery stenosis, and abdominal aorta aneurism progression. High 
serum Lp(a) concentration is genetically defined; it cannot be controlled by habit modifications 
and it is not effectively controlled by any of the currently available lipid-reducing medications. 
Therefore, the development of a novel agent to lower high Lp(a) concentrations is a valid 
approach to confer additional protection against CVD. Although definitive evidence that the 
reduction in serum Lp(a) will provide cardiovascular (CV) risk reduction is not yet available, 
Mendelian randomization epidemiologic studies, plasma lipid apheresis cohort results, and 
experimental data suggest a causal role for elevated Lp(a)22, 23, 24. 
The current nonclinical package supports conduct of a study in humans25. In nonclinical 
toxicology studies, Olpasiran was able to reduce Lp(a) levels, with no significant safety 
concerns identified. Olpasiran-related changes were limited to generally minimal to mild. Non 
adverse changes that were consistent with those expected for the modality. To date, based on 
nonclinical data, and safety data from Studies 20170544 and 20180222, there are no expected 
adverse drug reactions with Olpasiran and potential risks include hypersensitivity reactions and 
liver enzyme elevations.  
The benefit-risk assessment supports the conduct of this clinical study. Refer to the IB17 for 
more information. 
1.5.1 
Key Benefits 
Subjects in the current study will not receive any health benefit (beyond that of an assessment 
of their medical status) from participating in the study.  
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1.5.2 
Risks  
There are no identified adverse drug reactions for Olpasiran and important potential risks are 
limited to liver enzyme elevations and hypersensitivity reactions. Olpasiran is an 
oligonucleotide-based therapy, and events of interest associated with other antisense 
oligonucleotide (ASO)-based therapies include: effects on platelets and coagulation, immune-
inflammatory response, development of anti-drug antibodies, and peripheral neuropathy. 
Additionally, very low levels of Lp(a) have been associated with increased incidence of type 2 
diabetes, but whether pharmacologic lowering of Lp(a) would be associated with an increased 
risk for development of type 2 diabetes is unknown 26, 27. These risks have not been borne out 
by either the nonclinical data or clinical data to date for Olpasiran. Safety monitoring measures 
for these concerns have been implemented in the protocol. 
As stated in Section 1.3, no notable trends in safety and tolerability have been observed to date 
for Olpasiran in two clinical studies in human.  
Oligonucleotide-based therapies include ASOs and siRNAs. Key safety concerns associated 
with these products are further discussed below. Refer to the Olpasiran IB, Section 6.4, for 
additional information regarding safety concerns with related molecules. 
Hypersensitivity Reactions   
Administration of any drug may trigger hypersensitivity reactions. Immune-mediated 
hypersensitivity has been reported with biologics, including systemic and locally restricted 
reactions (including injection site reactions). ASO based therapies, including siRNAs, do not 
share molecular similarities with traditional amino acid-based biologics. Nevertheless, double 
stranded siRNA may be recognized by the innate immune system, triggering innate immune 
responses28. No hypersensitivity attributed to Olpasiran has been observed to date in clinical 
trials. 
Liver Enzymes Elevation 
ASOs, such as mipomersen, have been associated with liver enzyme elevations and hepatic 
steatosis. Olpasiran-related changes in the liver in the exploratory rat toxicology studies 
included hepatocellular vacuolation at all dose levels and, at higher dose levels, minimal to mild 
increased single cell necrosis of hepatocytes sometimes associated with increased mitoses. 
Hepatocellular mitoses are considered a regenerative response to the single cell necrosis. 
These liver changes were accompanied by transient, minimal increases in serum alanine 
aminotransferase (ALT). Minimal to mild increases in serum ALP and bilirubin were also 
observed. Olpasiran-related changes in the liver were considered to be siRNA platform -related 
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changes that were not adverse because of their low severity and ultrastructural characteristics. 
At the doses planned for administration in this study, organ toxicity related to intracellular 
accumulation is not expected. No safety concern for liver enzyme elevation and Olpasiran has 
been observed to date in clinical trials. 
During the study, safety monitoring based on organ target toxicity and other antisense toxicity29, 
30 will be conducted. Safety assessments throughout the study include TEAE and serious TEAE 
collection; physical examination, including assessment for peripheral neuropathy; monitoring for 
hypersensitivity reactions; ECGs; laboratory tests, including liver function tests; renal function 
tests; coagulation and hematologic parameters; metabolic acidosis, if needed; and glucose. 
Potential anaphylactic reactions will be assessed by Sampson criteria31. If Sampson criteria are 
positive, the potential anaphylactic reaction will be confirmed by measuring tryptase in blood 
plasma within 30 minutes of symptoms, if feasible. 
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objective of the study is: 
 
to evaluate the PK of a single dose of Olpasiran in Chinese subjects with elevated serum 
Lp(a).  
The secondary objectives of the study are: 
 
to evaluate the safety and tolerability of a single dose of Olpasiran in Chinese subjects 
with elevated serum Lp(a).  
 
to evaluate the PD of a single dose of Olpasiran in Chinese subjects with elevated 
serum Lp(a). 
2.2 
Endpoints 
2.2.1 
Primary Endpoints 
The primary endpoints of the study are Olpasiran PK parameters: 
 
Cmax 
 
AUC 
Additional PK parameters may include, but are not limited to: time to maximum observed 
concentration (tmax), half-life (t1/2), apparent volume of distribution during the terminal 
elimination phase (Vz/F), and apparent total body clearance (CL/F).  
2.2.2 
Secondary Endpoints 
The secondary endpoints of the study are: 
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 
treatment-emergent adverse events (TEAEs)   
 
clinical laboratory tests 
 
12-lead ECGs 
 
vital signs 
 
lipids 
 
serum Lp(a). 
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3. 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This study is an open-label, randomized, single-dose, parallel-group study in Chinese subjects 
with elevated serum Lp(a) to assess the PK, safety and tolerability, and PD of Olpasiran. 
Subjects will be randomized in a 1:1 ratio to receive a single SC dose of Olpasiran at 
 mg 
(Group A) or 
 mg (Group B). A total of approximately 24 subjects (12 per group) will be 
enrolled in this study.  
Subjects must be living in mainland China, Hong Kong, or Taiwan, and be of Chinese ancestry 
with an age of 18 to 60 years old (inclusive) and have body mass index of 18 to 32 kg/m2 
(inclusive) and serum Lp(a)  70 nmol/L (or approximately  27 mg/dL). 
Subjects will be assigned to 1 of 2 treatment groups shown in Table 1. 
Table 1.  Treatment Groups 
Group 
Number of subjects 
Dose 
A 
12 
 mg SC 
B 
12 
 mg SC 
Abbreviations: SC  subcutaneous. 
An overview of the study design is shown in Figure 1. The endpoints are defined in Section 2.2. 
Figure 1.  Study Schematic 
Abbreviations: SC  subcutaneous. 
Potential subjects will be screened to assess their eligibility to enter the study within 40 days 
prior to dose administration. Subjects will be admitted into the phase I Clinical Research Unit 
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(CRU) on Day -1 and be confined to the CRU until discharge on Day 4. Subjects will return to 
the CRU for outpatient visits on Days 7, 15, 29, 57, 85, 113, 155, and 183, and at the end of 
study (EOS) visit on Day 225. A telephone visit will be scheduled for TEAE assessments on Day 
211. The total duration of study participation for each subject (from Screening through EOS 
visit) is anticipated to be approximately 265 days (about 38 weeks).
The start of the study is defined as the date the first subject signs an Informed Consent Form 
(ICF). The point of enrollment occurs at the time of subject randomization number allocation. 
The enrollment date is the same as the randomization date. The EOS for overall study is 
defined as the date of the last subject’s last assessment (scheduled or unscheduled).  
A Schedule of Assessments is presented in Appendix 9. 
3.2 
Discussion of Study Design 
This study will be open-label. 
Conducting the study in subjects with elevated serum Lp(a) in Chinese subjects is necessary to 
support a comparison of Olpasiran PK parameters with those observed in the FIH study 
(20170544) and therefore to assess the ethnic difference, as baseline Lp(a) levels may impact 
Olpasiran exposure and the interpretation of these analyses. 
3.3 
Selection of Doses in the Study 
The selection of the doses for this study are supported by the dose margins determined from 
the NOAEL in rat and cynomolgus monkey (150 mg/kg). 
 
. These calculated dose margins are conservative as only a single 
dose will be given in this study, and the NOAEL was determined based on data from every 4-
week dosing (x3) in rat and cynomolgus monkey repeat-dose toxicology studies.   
The preliminary data from the FIH study (20170544) and the Japanese phase 1 PK study 
(20180222) indicated that Olpasiran is rapidly absorbed and eliminated with low, but detectable 
serum exposures, as expected for a siRNA oligonucleotide. Given the hepatic site target and 
rapid elimination of Olpasiran from systemic circulation, the dose-response relationship related 
to reductions in Lp(a) were used to support dose selection in this study and for future studies. 
The preliminary PD data demonstrated effective lowering of Lp(a) levels across the evaluated 
dose range of  mg and 
 mg, and with no identified safety concerns. 
In this study, the 
 and 
 mg SC doses are selected to evaluate the PK, PD, safety, and 
tolerability of Olpasiran in Chinese subjects with elevated serum Lp(a) levels. 
 
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. 
Evaluation of these 2 dose levels in the current study will allow a direct comparison of Olpasiran 
PK and Lp(a) reductions with those observed in FIH Study (20170544) in subjects with same 
screening Lp(a) levels  70 nmol/L. 
 
  
Therefore, the dose margins, the FIH study results, and the PK study in Japanese subjects 
support the selection of the dose levels to be evaluated in this study to assess the PK, PD, 
safety, and tolerability of Olpasiran, and to evaluate the magnitude and durability of Lp(a) 
reduction in Chinese subjects with elevated serum Lp(a).   
3.4 
End of Study 
Primary Completion: The primary completion date is defined as the date when the last subject 
is assessed or receives an intervention for the final collection of data for the primary endpoints 
(see Section 2.2.1), whether the study concluded as planned in the protocol or was terminated 
early. 
The primary completion date is the date when the last subject has completed the assessments 
on Day 225 of the study. 
If the study concludes prior to the primary completion date originally planned in the protocol (i.e., 
early termination of the study), then the primary completion will be the date when the last 
subject is assessed or receives an intervention for evaluation in the study (i.e., last subject last 
visit). 
End of Study: The EOS date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (i.e., last subject last visit), after 
any additional parts in the study (e.g., long-term follow-up), as applicable. 
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4. 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion Criteria 
Inclusion eligibility criteria will be evaluated in 2 parts during the screening period: 
 
Part 1: After written informed consent is obtained, subjects will provide a blood sample 
for a preliminary Lp(a) assessment to determine eligibility for Part 2 screening. Subjects 
with Lp(a)  70 nmol/L (or approximately  27 mg/dL) will be eligible to return to the CRU 
for Part 2 screening. Subjects not eligible to return for Part 2 screening will be screen 
failed. 
 
Part 2: Eligible subjects will complete all remaining screening procedures and tests that 
establish eligibility within 40 days prior to the Day 1 visit.  
To be eligible for the study, subjects must provide written informed consent to participate and 
must fulfill the following criteria:  
Inclusion Criteria (Part 1) 
1. Subject has provided informed consent before initiation of any study-specific 
activities/procedures. 
2. Must be a resident in mainland China, Hong Kong, or Taiwan, and of Chinese ancestry. 
3. Male or female subjects, between 18 and 60 years of age (inclusive) at the time of 
Screening. 
4. Screening serum Lp(a)  70 nmol/L (or approximately  27 mg/dL). 
Inclusion Criteria (Part 2) 
1. In good health, determined by no clinically significant findings from medical history, physical 
examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations 
(congenital nonhemolytic hyperbilirubinemia [e.g., suspicion of Gilbert’s syndrome based on 
total and direct bilirubin] is not acceptable) as assessed by the Investigator (or designee). 
2. Body mass index between 18 and 32 kg/m2 (inclusive) at the time of Screening. 
3. Subjects who are on statin must be on a stable dose of the same statin for at least 6 weeks 
prior to enrollment, and plan to remain on a stable dose (i.e., no change in medication or 
dosage) for the duration of the study 
4. Females must be of non-reproductive potential: 
a. Postmenopausal defined as: 
i. 
Age of  55 years with no menses for at least 12 months; OR 
ii. 
Age of  55 years with no menses for at least 12 months AND with a follicle 
stimulating hormone (FSH) level  40 IU/L or according to the definition of 
“postmenopausal range” for the laboratory involved; OR 
b. History of hysterectomy; OR 
c. History of bilateral oophorectomy 
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4.2 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria prior to 
enrollment unless otherwise stated: 
1. History or clinical evidence of peripheral neuropathy.  
2. Currently receiving apheresis as lipid reducing therapy. 
3. History or clinical evidence of bleeding diathesis or any coagulation disorder, including 
prothrombin time (PT), activated partial thromboplastin time (APTT), or platelet count 
outside of the laboratory’s normal reference range at screening. Subjects with PT and/or 
APTT values that are outside of the laboratory’s normal reference range at screening may 
still be eligible to proceed to enrollment if the results are judged by the investigator in 
consultation with the study medical monitor to not be clinically significant. 
4. History or clinical evidence of diabetes mellitus, including a fasting glucose  125 mg/dL 
(6.9 mmol/L) at Screening. 
5. History or evidence, at Screening or Check-in, of clinically significant disorder, condition, or 
disease not otherwise excluded that, in the opinion of the Investigator (or designee), would 
pose a risk to subject safety or interfere with the study evaluation, procedures, or 
completion. 
Exceptions include: 
a. Subjects with controlled and stable arterial hypertension. Controlled and stable 
hypertension with a systolic blood pressure [BP]  150 mmHg or diastolic BP 
 90 mmHg at Screening and Day -1, with no change in medication and dosage for 
at least 8 weeks prior to enrollment and expected to remain on this dose and 
medication for the entire duration of the study. If the initial BP is elevated, the reading 
may be repeated again at least 15 minutes later and the lower of the 2 readings may 
be used.  
b. Subjects with diagnosis of hyperlipidemia on treatment with a stable dose of the 
same statin (with or without concomitant ezetimibe) for at least 6 weeks prior to 
enrollment and expected to remain on this dose and medication for the entire 
duration of the study. 
6. A QT interval corrected for HR based on the Fridericia correction (QTcF) interval 
 450 msec in male subjects or  470 msec in female subjects or history/evidence of long 
QT syndrome, at Screening. 
7. Subject has known sensitivity to any of the products or components to be administered 
during dosing. 
8. Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 as calculated by the 
Modification of Diet in Renal Disease (MDRD) equation, at Screening. 
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)  1.1 x upper limit of 
normal (ULN), at Screening or Check-in. For subjects on a stable dose of statin, ALT or AST 
 1.5 x ULN of the laboratory’s reference at Screening or Check-in.  
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10. Positive hepatitis B or hepatitis C panel and/or positive human immunodeficiency virus 
antibodies test at Screening. Subjects whose results are compatible with prior immunity 
(vaccination or prior recovered infection) may be included. 
11. Use of any over-the-counter or prescription medications within 14 days or 5 half-lives 
(whichever is longer) before dosing on Day 1 and during the study is not permitted, unless to 
treat a TEAE. Continued use, if applicable, will be reviewed by the Principal Investigator (or 
designee) and in consultation with the Sponsor. Written documentation of this review and 
Sponsor acknowledgement is required for subject participation. Exceptions are: 
a. Acetaminophen (paracetamol) up to 2 g per day for analgesia  
b. Hormone replacement therapy (e.g., estrogen, thyroid) provided the subject is stable 
on replacement therapy 
c. Medication for the management of arterial hypertension, including, but not limited to, 
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta 
blockers, calcium channel blockers, or low dose thiazides, provided it is stable (i.e., 
no change in drug or dose) for at least 8 weeks prior to enrollment 
d. Use of anti-platelet therapy (low-dose acetylsalicylic acid [up to 162.5 mg daily], 
clopidogrel, or ticagrelor) is allowed, provided subjects have been on a stable dose 
for at least 6 weeks prior to enrollment and plan to be on the same dose for the 
duration of the study 
e. If subjects are on a statin, subjects must be on a stable dose of the same statin for at 
least 6 weeks prior to enrollment, and plan to remain on the same dose (i.e., no 
change in medication or dosage) for the duration of the study 
f. Use of ezetimibe is allowed, provided subjects have been on a stable dose for at 
least 6 weeks prior to enrollment and plan to be on the same dose for the duration of 
the study 
g. Medication used to manage chronic conditions not excluded by other exclusion 
criteria, provided subjects have been on a stable dose for at least 6 weeks prior to 
enrollment and plan to be on the same dose for the duration of the study. Medication 
must be reviewed and approved by the Investigator (or designee) and acknowledged 
by the Sponsor. Written documentation of this review and Sponsor 
acknowledgement is required for subject participation.  
12. Subjects are on niacin, or have received niacin  200 mg/day within 3 months prior to dosing 
on Day 1. 
13. Use of any herbal medicines, vitamins or dietary supplements known to affect lipid 
metabolism (e.g., fish oils  1000 mg/day, red yeast rice extract), within 30 days prior to 
dosing on Day 1 and for the duration of the study. 
14. All herbal medicines (e.g., St. John’s wort) and dietary supplements (with the exception of 
those known to affect lipid metabolism, which are excluded above) consumed by the subject 
within the 30 days prior to Check-in, unless deemed acceptable by the Investigator (or 
designee) and in consultation with the Sponsor. 
15. Triglycerides  5.65 mmol/L (i.e., 500 mg/dL) at Screening 
16. History of drug/chemical abuse within 1 year prior to Check-in. 
17. Alcohol consumption within 48 hours prior to Check-in and during in-house residency period. 
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18. Alcohol consumption of  14 units per week for males and  7 units per week for females. 
One unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) 
wine. 
19. Positive test for illicit drugs and/or alcohol use at Screening or Check-in.  
20. Female subjects with a positive pregnancy test at Screening or Check-in.  
21. Female subjects lactating/breastfeeding or who plans to breastfeed during the study through 
90 days after Olpasiran dosing. 
22. Unwilling to abstain from sperm donation through 90 days after Olpasiran dosing (see 
Appendix 4). 
23. Male subjects with a female partner of childbearing potential and not willing to inform his 
partner of his participation in this clinical study. 
24. Male subjects with a pregnant partner or partner planning to become pregnant while the 
subject is on study through 90 days after Olpasiran dosing. 
25. Subject has received a dose of an investigational drug within the past 30 days or 5 half-
lives, whichever is longer, prior to Check-in. Other investigational procedures while 
participating in this study are excluded. 
26. Have previously completed or withdrawn from this study or any other study investigating 
Olpasiran or have previously received the investigational product.  
27. Donation of blood from 60 days prior to Check-in, plasma from 2 weeks prior to Check-in, or 
platelets from 6 weeks prior to Check-in. 
28. Performed strenuous exercise within 72 hours prior to Screening or Check-in. 
29. Unwilling to abide with study restrictions. 
30. Subjects who, in the opinion of the Investigator (or designee), should not participate in this 
study. 
4.3 
Screen Failures and Rescreening 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently enrolled (i.e., randomized) into the study. A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility criteria, 
medical history, prior therapies, and any serious TEAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Refer to Section 7.1.1. 
4.4 
Subject Number and Identification  
Subjects will have a unique identification number used at screening. Subjects will be assigned a 
unique subject number at randomization. Assignment of subject numbers will be in ascending 
order and no numbers will be omitted (e.g., Subjects 0101, 0102, 0103). Replaced subjects will 
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be assigned a subject number corresponding to the number of the subject he/she is replacing 
plus 1000 (e.g., Subject 1101 replaces Subject 0101). 
Subjects will be identified by subject number only on all study documentation. A 1-digit site 
identification number will be added to the subject number when entering the subject into the 
database (example: site 1, Subject 0101 will be entered as 10101 into the database). A list 
identifying the subjects by subject number will be kept in the Site Master File. 
4.5 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be withdrawn 
if any of the following criteria are met: 

change in compliance with any inclusion/exclusion criterion that is clinically relevant and
affects subject safety as determined by the Investigator (or designee)

noncompliance with the study restrictions that might affect subject safety or study
assessments/objectives, as considered applicable by the Investigator (or designee)

any clinically relevant sign or symptom that, in the opinion of the Investigator (or
designee), warrants subject withdrawal.
If a subject is withdrawn after randomization and prior to receiving Olpasiran dose, the Sponsor 
will be notified and the date and reason(s) for the withdrawal will be documented in the subject’s 
electronic Case Report Form (eCRF). If a subject is withdrawn, efforts will be made to perform 
all EOS assessments, if possible (Appendix 9). Other procedures may be performed at the 
Investigator’s (or designee’s) and/or Sponsor’s discretion. If the subject is in-house, these 
procedures should be performed before the subject is discharged from the CRU. The 
Investigator (or designee) may also request that the subject return for additional follow-up visits. 
All withdrawn subjects will be followed until resolution of all their TEAEs or until the unresolved 
TEAEs are judged by the Investigator (or designee) to have stabilized. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion between the Investigator and the Sponsor. Subjects withdrawn as a result of TEAEs 
thought to be related to the study drug will generally not be replaced. 
4.6 
Study Termination 
The Sponsor may stop the study or study site participation in the study for medical, safety, 
regulatory, administrative, or other reasons consistent with applicable laws, regulations, and 
GCP. Both the Sponsor and the Investigator reserve the right to terminate the Investigator's 
participation in the study according to the Clinical Trial Agreement. The Investigator is to notify 
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the Ethics Committee (EC) in writing of the study's completion or early termination and send a 
copy of the notification to the Sponsor.  
In addition, the study may be terminated by the Sponsor at any time and for any reason. If the 
Sponsor decides to terminate the study, the Sponsor will inform the Investigator as soon as 
possible. 
5. 
STUDY TREATMENTS 
Study treatment is defined as the investigational product intended to be administered to a study 
subject according to the study protocol. 
The Investigational Product Instruction Manual (IPIM), a document external to this protocol, 
contains detailed information regarding the storage, preparation, destruction, and administration 
of the investigational medicinal product (IMP) shown in Table 2 and Appendix 8 
5.1 
Investigational Product 
The IMP will be supplied by the Sponsor.  
All supplies of investigational product, both bulk and subject-specific, will be stored in 
accordance with the manufacturer’s instructions or pharmacy instructions. Until dispensed to the 
subjects, the investigational products will be stored at the study site in a location that is locked 
with restricted access. 
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Table 2.  Investigational Product 
Amgen Investigational Medicinal Producta 
Study Treatment 
Name 
Olpasiran (Group A) 
Olpasiran (Group B) 
Unit Strength and 
Formulation 
 mg/mL vialb 
Olpasiran SC injection 
 mg/mL vialb 
Olpasiran SC injections 
Dosage Level 
 mg (
 
 mg (
) 
Route of 
Administration 
SC injection 
SC injection 
Accountability 
The date/time of administration, 
lot number, box number of 
investigational product is to be 
recorded on each subject's 
CRF(s). 
The Investigator or study 
physician must be available when 
the subject receives the dose of 
Olpasiran for immediate 
intervention in case of 
complication(s). 
The date/time of administration, 
lot number, box number of 
investigational product is to be 
recorded on each subject's 
CRF(s).
 
 
. 
The Investigator or study 
physician must be available when 
the subject receives the dose of 
Olpasiran for immediate 
intervention in case of 
complication(s). 
Abbreviations: CRF  case report form; SC  subcutaneous. 
a Olpasiran will be manufactured and packaged by Amgen and distributed using Amgen clinical study 
drug distribution procedures.  
b Provided as a 
, with maximum deliverable volume of up to 
 
 from each vial of 
 mg/mL Olpasiran. Each
mL).
.  
5.2 
Treatment of Overdose 
Treatment overdose is not applicable to this study. 
5.3 
Randomization 
Subjects will be randomized in a 1:1 ratio to 1 of 2 groups (A or B) as shown in Table 1, in an 
open-label manner. 
Labcorp will provide a computer-generated randomization schedule to the site to be used for 
treatment assignments. Subjects will be assigned a subject number based in sequential order in 
which they qualified to be randomized, in accordance with the randomization schedule. Subjects 
are considered randomized once a unique subject number has been assigned. Dosing should 
occur within 1 day ( 24 hours) of randomization. If dosing cannot occur within 1 day of 
randomization, the Medical Monitor may be contacted to approve dosing outside the 24-hour 
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window (up to an additional 24 hours after randomization). The randomization date is to be 
documented in the subject’s medical record and on the enrollment CRF. 
5.4 
Blinding 
This is an open label study; blinding procedures are not applicable.  
5.5 
Treatment Compliance 
Treatment compliance is not applicable to this study. 
5.6 
Drug Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, or 
return of the investigational product during the study are provided in the IPIM. 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1 
Concomitant Therapies 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for the following: 
 
Use of any over-the-counter or prescription medications within 14 days or 5 half-lives 
(whichever is longer), before dosing on Day 1 and during the study, unless to treat a TEAE 
 
Use of any herbal medicines, vitamins, or dietary supplements known to affect lipid 
metabolism (e.g., fish oils  1000 mg/day, red yeast rice extract), within 30 days before 
dosing on Day 1 and for the duration of the study. 
The following concomitant therapies are allowed: 
 
Acetaminophen (paracetamol) up to 2 g/day for analgesia 
 
Hormone replacement therapy (e.g., estrogen, thyroid) provided the subject is stable on 
replacement therapy 
 
Medication for the management of arterial hypertension, including, but not limited to, 
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, 
calcium channel blockers, or low dose thiazides, provided it is stable (i.e., no change in 
drug or dose) for at least 8 weeks prior to enrollment 
 
Use of anti-platelet therapy (low-dose acetylsalicylic acid [up to 162.5 mg daily], 
clopidogrel, or ticagrelor) is allowed, provided subjects have been on a stable dose for at 
least 6 weeks prior to enrollment and plan to be on the same dose for the duration of the 
study 
 
If subjects are on statin, subjects must be on a stable dose of the same statin for at least 
6 weeks prior to enrollment, and plan to remain on the same dose (i.e., no change in 
medication or dosage) for the duration of the study 
 
Use of ezetimibe is allowed, provided subjects have been on a stable dose for at least 
6 weeks prior to enrollment and plan to be on the same dose for the duration of the 
study 
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 
Medication used to manage chronic conditions not excluded by other exclusion criteria, 
provided subjects have been on a stable dose for at least 6 weeks prior to enrollment 
and plan to be on the same dose for the duration of the study. Medication must be 
reviewed and approved by the Investigator (or designee) and acknowledged by the 
Sponsor. Written documentation of this review and Sponsor acknowledgement is 
required for subject participation. 
 
All herbal medicines (e.g., St. John’s wort) and dietary supplements (with the exception 
of those known to affect lipid metabolism, which are excluded above) consumed by the 
subject within the 30 days prior to Check-in and continue use during the study, which are 
deemed acceptable by the Investigator (or designee) and in consultation with the 
Sponsor. 
Concomitant therapies are to be collected from informed consent through the EOS. Any 
medication taken by a subject during the course of the study and the reason for its use will be 
documented in the source data.  
6.2 
Diet 
While confined at the study site, subjects will receive a standardized diet at scheduled times that 
do not conflict with other study-related activities. Subjects will be fasted overnight (at least 
10 hours) before collection of blood samples for clinical chemistry evaluations or lipids. 
Alcohol consumption will not be allowed from 48 hours prior to Check-in until end of in-house 
residency period.  
6.3 
Exercise 
Subjects will abstain from strenuous exercise for 72 hours before each blood collection for 
clinical laboratory tests. Subjects may participate in light recreational activities during the study 
(e.g., watching television, walking, reading). 
6.4 
Blood Donation 
Subjects are required to refrain from donation of blood from 60 days prior to Check-in, plasma 
from 2 weeks prior to Check-in, and platelets from 6 weeks prior to Check-in until 3 months after 
the EOS visit.  
7. 
STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving consideration to appropriate posture conditions, practical restrictions, and 
the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
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 
PK blood samples 
 
safety assessments (ECGs will be scheduled before vital signs measurements) 
 
any other procedures. 
Where activities at a given timepoint coincide, consideration must be given to ensure that the 
following order of activities is maintained: blood samples, ECGs, vital signs, and other 
procedures. 
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the subject is to continue or discontinue study 
treatment. 
Adherence to the study design requirements, including those specified in the Schedule of 
Assessments, is essential and required for study conduct. 
7.1 
Study Procedures 
7.1.1 
Screening, Enrollment, and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy. After the subject has signed the 
ICF, the site will screen the subject to assess eligibility for participation. The screening window 
is up to 40 days. 
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, see 
Section 4.3 as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the subject will 
be registered as a screen failure. Screen failed subjects may be eligible for re-screening 3 
times. 
Once the subject is registered as rescreened, a new 40-day screening window will begin. 
Subjects will retain the same unique identification number assigned at the original screening. If 
the rescreening period begins more than 40 days after the original signing of the ICF, all 
screening procedures, including informed consent, must be repeated as well. 
Laboratory assessments used to determine subject eligibility may be repeated once for 
confirmation, allowing for up to a total of two assessments during the 40-day screening period, if 
necessary, before the subject is considered a screen failure. If any assessments are repeated 
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during the screening period, the value that is closest to the enrollment date will apply for the 
determination of eligibility.  
If the initial BP measurement is elevated, the assessment may be repeated again at least 
15 minutes later and the lower of the 2 readings may be used for Screening. 
Subjects will be assigned a randomization number based in sequential order in which they 
qualified to be randomized, in accordance with the randomization schedule. Subjects are 
considered randomized once a unique subject randomization number has been assigned.  
The point of enrollment occurs at the time of subject randomization number allocation. The 
enrollment date is the same as the randomization date.  
7.1.2 
Treatment Period  
Dosing should occur within 1 day ( 24 hours) of randomization. Visits will occur per the 
Schedule of Assessments in Appendix 9. The date of the dose of Olpasiran is defined as Day 1. 
All subsequent study visits will be scheduled based on the Day 1 date. 
7.1.3 
End of Study 
Subjects’ participation in the study will conclude with the completion of the EOS procedures 
unless any study assessment demonstrates a significant clinical or laboratory abnormality. The 
subject will be followed until resolution of the abnormality or until the subject is considered 
clinically stable by the principal investigator. EOS procedures may be performed on subjects 
who are withdrawn early from the study. 
7.2 
General Assessments 
7.2.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the EC 
approved ICF before any study-specific procedures are performed. 
7.2.2 
Demographics 
Demographic data collection including sex and age will be collected. 
7.2.3 
Physical Examination 
Physical examination will be performed and will include a neurological examination (breast, 
rectal and genital examination are not required). Physical examination findings should be 
recorded on the appropriate CRF (e.g., medical history, TEAE). 
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7.2.4 
Physical Measurements 
Height [in centimeters] should be measured without shoes. Weight [in kilograms] should be 
measured without shoes. Body Mass Index should be calculated using the following formula: 
BMI (kg/m2)  weight (kg)/[height (cm)/100]2. 
7.2.5 
Medical History 
The Investigator or designee will collect a complete medical history at screening and an interim 
medical history at Check-in. Medical history will include information on the subject's concurrent 
medical conditions and subjects’ use of tobacco, alcohol, and history of non-reproductive 
potential. Record all findings on the medical history CRF. 
7.3 
Pharmacokinetic Assessments 
7.3.1 
Pharmacokinetic Blood Sample Collection and Processing 
All subjects enrolled will have PK samples assessed. Blood samples of approximately 4 mL will 
be collected for measurement of serum concentrations of Olpasiran by venipuncture or 
cannulation at the times indicated in the Schedule of Assessments in Appendix 9.  
Instructions for the collection and handling of biological samples will be provided by the sponsor. 
The actual date and time (24-hour clock time) of each sample will be recorded. 
7.3.2 
Analytical Methodology 
Serum concentrations of Olpasiran will be determined using validated analytical procedures. 
Specifics of the analytical method will be provided in a separate document.  
7.4 
Pharmacodynamic Assessments 
7.4.1 
Pharmacodynamic Blood Sample Collection and Processing 
Venous blood samples (approximately 5 mL) will be collected for measurement of Lp(a) at times 
indicated in the Schedule of Assessments in Appendix 9.  
Lipid panel will include triglycerides, VLDL-C, LDL-C, and HDL-C, total cholesterol, ApoA1, and 
total Apo B. At Screening, lipids will measure triglycerides only. Subjects will be fasted overnight 
(at least 10 hours) before collection of blood samples for lipids. Venous blood samples 
(approximately 8.5 mL) will be collected for measurement of lipids at the times indicated in the 
Schedule of Assessments in Appendix 9.  
7.4.2 
Analytical Methodology 
Serum concentrations of Lp(a) and lipids will be determined using validated analytical 
procedures. Specifics of the analytical method will be provided in a separate document. 
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7.5 
Anti-Olpasiran Antibody Assessments 
Bioanalytical testing for anti-Olpasiran antibodies will be conducted on blood samples 
(approximately 4 mL) at times indicated in the Schedule of Assessments in Appendix 9, if there 
are unexpected PK or PD findings or antibody-related safety concerns in this study. Samples 
testing positive may be further characterized. Additional blood samples may be obtained to rule 
out anti-Olpasiran antibodies during the study.  
Subjects who test positive for binding antibodies at the final antibody-scheduled timepoint and 
have clinical sequelae that are considered potentially related to an anti-Olpasiran antibody 
response may also be asked to return for additional follow-up testing.  
7.6 
Safety and Tolerability Assessments 
7.6.1 
Treatment-Emergent Adverse Events and Serious Treatment-Emergent 
Adverse Events: Time Period and Frequency for Collecting and Reporting 
Safety Event Information 
TEAE definitions, assignment of severity and causality, and procedures for reporting serious 
TEAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to EOS visit. 
Subjects will be observed for any signs or symptoms and asked about their condition by open 
questioning, such as “How have you been feeling since you were last asked?”, at least once 
each day while resident at the study site and at each study visit. Subjects will also be 
encouraged to spontaneously report TEAEs occurring at any other time during the study. 
Treatment-emergent adverse events 
The TEAE grading scale to be used in this study is described in “Assessment of Severity” in 
Appendix 1. 
The Investigator is responsible for ensuring that all non-serious TEAEs observed by the 
Investigator or reported by the subject (whether reported by the subject voluntarily or upon 
questioning or noted on physical examination) from Olpasiran dosing through EOS are 
recorded/reported using the appropriate eCRF. 
Serious treatment-emergent adverse events 
The Investigator is responsible for ensuring that all serious TEAEs observed by the Investigator 
or reported by the subject that occur after signing of the ICF through 30 days after the dosing or 
the EOS visit (whichever is later) are reported using the appropriate eCRF and reported on the 
Serious Treatment-Emergent Adverse Event Report Form (described in Appendix 1). 
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All serious TEAEs will be collected, recorded, and reported to the Sponsor within 24 hours of 
the Investigator’s knowledge of the event. The Investigator will submit any updated serious 
TEAE data to the Sponsor within 24 hours of it being available. 
Serious Treatment-emergent Adverse Events after the Protocol-Required Reporting 
Period  
There is no requirement to monitor study subjects for serious TEAEs following the protocol 
required reporting period or after EOS. However, these serious TEAEs can be reported to 
Amgen. Per local requirements in some countries, Investigators are required to- report serious 
TEAEs that they become aware of after EOS. If serious TEAEs are reported, the Investigator is 
to report them to the Sponsor within 24 hours following the Investigator’s knowledge of the 
event using the Serious Treatment-Emergent Adverse Event Report Form (Figure 2). 
Serious TEAEs reported outside of the protocol-required reporting period will be captured within 
the Sponsor’s safety database as clinical trial cases and handled accordingly based on 
relationship to investigational product. 
Method of Detecting Treatment-emergent adverse events and Serious Treatment-
emergent adverse events 
Care will be taken not to introduce bias when detecting TEAEs and/or serious TEAEs. Open-
ended and nonleading verbal questioning of the subject is the preferred method to inquire about 
TEAE occurrence. 
Follow-up of Treatment-emergent adverse events and Serious Treatment-emergent 
adverse events 
After the initial TEAE/serious TEAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All TEAEs and serious TEAEs will be followed, where 
possible, until resolution, stabilization, until the event is otherwise explained, or the subject is 
lost to follow-up. This will be completed at the Investigator’s (or designee’s) discretion. 
All new information for previously reported serious TEAEs must be sent to Amgen within 
24 hours following knowledge of the new information. If specifically requested, the Investigator 
may need to provide additional follow-up information, such as discharge summaries, medical 
records, or extracts from the medical records. Information provided about the serious TEAE 
must be consistent with that recorded on the eCRF. 
Regulatory Reporting Requirements for Serious Treatment-emergent adverse events 
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If subject is permanently withdrawn from protocol-required therapies because of a serious 
TEAE, this information must be submitted to the Sponsor. 
Prompt notification by the Investigator to the Sponsor of serious TEAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
treatment under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, ECs, and Investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to Investigators as 
necessary. 
An Investigator who receives an individual safety report describing a serious TEAE or other 
specific safety information (e.g., summary or listing of serious TEAEs) from the Sponsor will file 
it along with the IB and will notify the EC, if appropriate according to local requirements. 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in the Sponsor’s safety surveillance and 
signal management processes. 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and pregnancies in female partners 
of male subjects will be collected until 90 days after Olpasiran dosing. 
If a pregnancy and/or lactation is reported, the Investigator is to inform Amgen within 24 hours 
of learning of the pregnancy and/or lactation and is to follow the procedures outlined in 
Appendix 5. Amgen Global Patient Safety will follow-up with the Investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (e.g., female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) are considered 
serious TEAEs. 
Further details regarding pregnancy and lactation are provided in Appendix 5. 
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7.6.2 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
coagulation panel, clinical chemistry, hematology, urinalysis, serology, and eGFR) at the times 
indicated in the Schedule of Assessments in Appendix 9. Clinical laboratory evaluations are 
listed in Appendix 2 Table 3. Blood will be collected after fasting at least 10 hours for clinical 
chemistry evaluations. 
The Investigator is responsible for reviewing laboratory test results and recording any clinically 
relevant changes occurring during the study in CRF/eCRF. The Investigator must determine 
whether an abnormal value in an individual study subject represents a clinically significant 
change from the subject’s baseline values. In general, abnormal laboratory findings without 
clinical significance (based on the Investigator’s judgment) are not to be recorded as TEAEs. 
However, laboratory value changes that require treatment or adjustment in current therapy are 
considered TEAEs. Where applicable, clinical sequelae (not the laboratory abnormality) are to 
be recorded as the TEAE. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, and 
will undergo an alcohol urine test at the times indicated in the Schedule of Assessments in 
Appendix 9. For all female subjects, a pregnancy test and FSH screen for postmenopausal 
women will be performed at the times indicated in the Schedule of Assessments in Appendix 9. 
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
Pregnancy test 
A highly sensitive serum pregnancy test should be completed at screening for all female 
subjects. A urine pregnancy test should be completed at all other times. A positive urine 
pregnancy test will be confirmed with a serum pregnancy test. A pregnancy test should be 
performed at the end of the study. (If a female subject, or the partner of a male subject, 
becomes pregnant it must be reported on the Pregnancy Notification Form, see Figure 3). Refer 
to Appendix 4 for contraceptive requirements. Additional on-treatment pregnancy testing may be 
performed at the investigator’ discretion or as required per local laws and regulations. 
eGFR 
eGFR will be calculated using the MDRD equation. 
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7.6.3 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at least 
5 minutes at the times indicated in the Schedule of Assessments in Appendix 9. If the subject is 
unable to be in the supine position, the subject should be in the most suitable recumbent 
position possible. The ECG must include the following measurements: heart rate, QRS, QT, 
QTc, and PR intervals. The ECG will be single trace (1 x 10-second tracing), prior to safety 
blood draws or invasive procedures. 
Single 12-lead ECGs will be repeated twice (within a total of five minutes from the start of the 
first to the completion of the third), and an average taken of the 3 readings, if either of the 
following criteria apply: 
 
QTcF is  500 ms 
 
QTcF change from the baseline (predose) is  60 ms. 
The Investigator (or designee [e.g., designated site physician]) will review all ECGs. Once 
signed, the original ECG tracing will be retained with the subject’s source documents. At the 
request of the sponsor, a copy of the original ECG will be made available to Amgen. Additional 
12lead ECGs may be performed at other times if judged to be clinically appropriate or if the 
ongoing review of the data suggests a more detailed assessment of ECGs is required. The 
investigator (or designee) will perform a clinical assessment of each 12-lead ECG. 
7.6.4 
Vital Signs 
Systolic/diastolic BP, pulse rate, respiratory rate, and body temperature will be assessed in 
sitting position at the times indicated in the Schedule of Assessments in Appendix 9. Pulse rate 
and BP will be measured using the same arm for each reading after the subject has been 
resting in the sitting position for at least 5 minutes. Vital signs may also be performed at other 
times if judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of vital signs is required. The position selected for a subject should be the 
same position used throughout the study and documented on the vital sign CRF. 
All measurements will be performed singly and repeated once (within a total of 5 minutes) if 
outside the relevant clinical reference range. 
Subjects must be sitting for at least 5 minutes before BP and pulse rate measurements. When 
vital signs are scheduled at the same time as blood draws, the blood draws will be obtained at 
the scheduled timepoint, and the vitals will be obtained as close to the scheduled blood draw as 
possible, but preferably prior to the safety blood draw. 
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8. 
SAMPLE SIZE AND DATA ANALYSIS 
Data will be analyzed for all subjects who are randomized and receive Olpasiran. Descriptive 
statistics by treatment group will be provided for selected demographics, safety, PK and Lp(a) 
data. Descriptive statistics on continuous measurements will include means, medians, standard 
deviations, and ranges, while categorical data will be summarized using frequency counts and 
percentages. PK, Lp(a), lipids (as listed in Table 4 in Appendix 2), vital signs, ECG, and clinical 
laboratory data will be summarized at each scheduled visit per Schedule of Assessments. 
Additional details will be included in the Statistical Analysis Plan (SAP). 
8.1 
Determination of Sample Size 
Approximately 24 subjects (12 per group) will be enrolled in the study. No formal statistical 
hypothesis testing will be performed. The sample size of 12 subjects per group is based on 
studies of similar nature and is not based on power calculations. Considering a 33.3 drop-out 
rate, 8 subjects per cohort provides an approximately 90 confidence of observing a case of a 
TEAE in each cohort at an incidence of 25.  
8.2 
Analysis Set 
8.2.1 
Pharmacokinetic Analysis Set 
The PK analysis set will include all randomized subjects who received Olpasiran and have 
evaluable PK data.  
8.2.2 
Pharmacodynamic Analysis Set 
The PD analysis set will include all randomized subjects who received Olpasiran and have 
evaluable PD data. 
8.2.3 
Safety Analysis Set 
The safety analysis set will include all randomized subjects who received Olpasiran. 
8.3 
Pharmacokinetic Analyses 
The serum PK parameters of Olpasiran will be calculated using standard noncompartmental 
methods. Pharmacokinetic parameters will be listed and summarized using descriptive 
statistics. 
Additional statistical analyses may be performed as appropriate. Detailed descriptions of the 
statistical analysis and reporting of data will be provided in the SAP. 
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8.4 
Pharmacodynamic Analyses 
Absolute change and percent change in serum Lp(a) and lipids from baseline will be 
summarized by treatment groups. 
Detailed descriptions of the statistical analysis and reporting of data will be presented in the 
SAP for this study. 
8.5 
Safety Analysis 
The final safety analysis for the study will be performed at the end of the study. No imputation 
will be done for safety assessments and endpoints for clinical laboratory tests, 12-lead ECGs, 
and vital signs will be summarized using descriptive statistics.  Each TEAE will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Subject incidence of all TEAEs will 
be tabulated by system organ class and preferred term and by treatment group. Subject 
incidence tables of fatal TEAEs and serious TEAEs will be tabulated by treatment group. 
Subject-level data may be provided instead of tables if the subject incidence is low.  
8.6 
Interim Analysis 
No interim analyses are planned for this study.  
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9. 
REFERENCES 
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4. Mendes de Leon CF, Krumholz HM, Vaccarino V, et al. A population-based perspective of 
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5. Schweikert B, Hunger M, Meisinger C, et al. Quality of life several years after myocardial 
infarction: comparing the MONICA/KORA registry to the general population. Eur Heart J. 
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6. Simpson E, Pilote L. Quality of life after acute myocardial infarction: a systematic review. 
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7. Mollon L, Bhattacharjee S. Health related quality of life among myocardial infarction 
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8. Kassner U, Schlabs T, Rosada A. Lipoprotein(a)-An independent causal risk factor for 
cardiovascular disease and current therapeutic options. Atheroscler Suppl. 2015;18:263–
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9. Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of 
cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. 
J Am Coll Cardiol. 2014;64:851-860. 
10. Jacobson TA. Lipoprotein(a). Cardiovascular Disease, and Contemporary Management. 
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years. Curr Opin Lipidol. 2012;23(2):133–140. 
13. Schmidt K, Noureen A, Kronenberg F, et al. Structure, function, and genetics of lipoprotein 
(a). J Lipid Res. 2016;57:1339-1359. 
14. Marcovina SM, Albers JJ, Scanu AM, et al. Use of a reference material proposed by the 
International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical 
methods for the determination of plasma lipoprotein(a). Clin Chem. 2000;46(12):1956-1967. 
15. Ellis KL, Boffa MB, Sahebkar A, et al. The renaissance of lipoprotein(a): Brave new world for 
preventive cardiology? Prog Lipid Res. 2017;68: 57-82. 
16. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: 
insights from epidemiology, genetics, and biology. J Lipid Res. 2016;57:1953-1975. 
17. Amgen Inc. Olpasiran (AMG 890) – Investigator’s Brochure. (Version 4.0). 06 January 2021. 
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18. Janas MM, Harbison CE, Perry VK, et al. The Nonclinical Safety Profile of 
GalNAc-conjugated RNAi Therapeutics in Subacute Studies. Toxicol Pathol. 
2018;46(7):735-745. 
19. Frazier KS. Antisense oligonucleotide therapies: the promise and the challenges from a 
toxicologic pathologist’s perspective. Toxicol Pathol. 2014;43(1):78-89. 
20. Crooke, S. (Ed.). Antisense Drug Technology: Principles, Strategies and Applications. 2nd 
ed. CRC Press; 2008. 
21. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—2015 
update: a report from the American Heart Association. Circulation. 2015;131(4):e29-322. 
22. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein 
level and coronary disease. N Engl J Med. 2009;361(26):2518-2528. 
23. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically elevated lipoprotein(a) 
and increased risk of myocardial infarction. JAMA. 2009;301:2331-2339. 
24. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al. Lipoprotein(a) 
concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. 
JAMA. 2009;302(4):412-423. 
25. Roeseler E, Julius U, Heigl F, et al. Lipoprotein apheresis for lipoprotein(a)-associated 
cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) 
characterization. Arterioscler Thromb Vasc Biol. 2016;36:2019–2027. 
26. Paige E, Masconi KL, Tsimikas S, et al. Lipoprotein(a) and incident type-2 diabetes results 
from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc 
Diabetol. 2017;16(1):38.  
27. Ye Z, Haycock PC, Gurdasani D, et al. The association between circulating lipoprotein(a) 
and type-2 diabetes: is it causal? Diabetes. 2014;63(1):332-342. 
28. Singh A, Trivedi P, Jain NK. Advances in siRNA delivery in cancer therapy. Artif Cells 
Nanomed Biotechnol. 2018;46:274-283. 
29. Chi X, Gatti P, Papoian T. Safety of antisense oligonucleotide and siRNA-based 
therapeutics. Drug Discov Today. 2017;22:823-833. 
30. Dobrovolskaia MA, McNeil SE. Immunological and hematological toxicities challenging 
clinical translation of nucleic acid-based therapeutics. Expert Opin Biol Ther. 
2015;15(7):1023-1048 
31. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition 
and management of anaphylaxis: summary report--second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 
2006;47(4):373-380. 
32. Food and Drug Administration. Guidance for Industry: Drug-Induced Liver Injury - 
Premarketing Clinical Evaluation [Internet]. 2009. Available at: 
https://www.fda.gov/media/116737/download  
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10. 
APPENDICES 
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Appendix 1.  Safety Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting of Treatment-emergent adverse event 
Definition of Treatment-emergent adverse event 
Treatment-emergent adverse event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment. 
 
Note: An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device, or procedure. 
 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts 
during or after the first dose or starts prior to the first dose and increases in 
severity after the first dose. 
Events Meeting the Treatment-emergent adverse event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., electrocardiogram, radiological scans, vital 
signs measurements), including those that worsen from baseline, that are 
considered clinically significant in the medical and scientific judgment of the 
Investigator (i.e., not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as a 
TEAE/serious TEAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses are to be reported regardless of 
sequelae. 
Events NOT Meeting the Treatment-emergent adverse event Definition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the TEAE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Treatment-emergent adverse event 
A Serious Treatment-emergent adverse event is defined as any untoward 
medical occurrence that meets at least 1 of the following serious criteria: 
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Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death if it were more severe. For instance, 
drug induced-hepatitis that resolved without evidence of hepatic failure would not be 
considered life threatening even though drug induced-hepatitis can be fatal. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are a TEAE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
considered serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the TEAE is to be considered serious. Hospitalization for elective treatment 
of a pre-existing condition that did not worsen from baseline is not considered a TEAE. 
Results in persistent or significant disability/incapacity 
The term “disability” means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious TEAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 1 of 
the other outcomes listed in the above definition. These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Recording Treatment-emergent adverse events and Serious Treatment-emergent adverse 
events 
Treatment-emergent adverse event and Serious Treatment-emergent adverse 
event Recording 
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 
When a TEAE or serious TEAE occurs, it is the responsibility of the Investigator to 
review all documentation (e.g., hospital progress notes, laboratory, and diagnostics 
reports) related to the event. 
 
The Investigator will then record all relevant TEAE/serious TEAE information in the 
Event electronic Case Report Form (eCRF). 
 
The Investigator must assign the following TEAE attributes: 
o TEAE diagnosis or syndrome(s), if known (if not known, signs or symptoms); 
o Dates of onset and resolution (if resolved); 
o Severity (or toxicity defined below); 
o Assessment of relatedness to the investigational product(s) and/or study-
mandated procedures, and 
o Action taken. 
 
If the severity of a TEAE changes from the date of onset to the date of resolution, 
record the TEAE as a single event with the worst severity on the appropriate 
eCRF.  
 
It is not acceptable for the Investigator to send photocopies of the subject’s 
medical records to Sponsor in lieu of completion of the appropriate eCRF page. 
 
If specifically requested, the Investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records. In this case, all subject identifiers, with the exception of- the 
subject number, will be blinded on the copies of the medical records before 
submission to the Sponsor. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as a TEAE/serious TEAE. 
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Evaluating Treatment-emergent adverse events and Serious Treatment-emergent adverse 
events 
Assessment of Severity 
The Investigator will make an assessment of severity for each TEAE and serious 
TEAE reported during the study. The assessment of severity will use the following 
definitions:  
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated, usually transient and 
may require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily living. 
MODERATE 
Discomfort enough to cause interference with usual activity causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. Usually alleviated with additional specific therapeutic 
intervention. 
SEVEREa 
Incapacitating with inability to work or interrupts usual activities of 
daily living, or significantly affects clinical status, or may require 
intensive therapeutic intervention. 
a An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of a serious TEAE, NOT when it is rated as severe. 
Assessment of Causality 
 
The Investigator is obligated to assess the relationship between investigational 
product(s), protocol-required therapy and/or study-mandated procedure and each 
occurrence of each TEAE/serious TEAE. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product and the event. 
 
The Investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The Investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each TEAE/serious TEAE, the Investigator must document in the medical 
notes that he/she has reviewed the TEAE/serious TEAE and has provided an 
assessment of causality. 
 
There may be situations in which a serious TEAE has occurred, and the 
Investigator has minimal information to include in the initial report. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the serious TEAE data. 
 
The Investigator may change his/her opinion of causality in light of follow-up 
information and send a serious TEAE follow-up report with the updated causality 
assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
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Follow-up of Treatment-emergent adverse event and Serious Treatment-
emergent adverse event 

The Investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by the
Sponsor to elucidate the nature and/or causality of the TEAE or serious TEAE as
fully as possible. This may include additional laboratory tests or investigations,
histopathological examinations, or consultation with other health care
professionals.

If a subject is permanently withdrawn from protocol-required therapies because of
a serious TEAE, this information must be submitted to the Sponsor.

If a subject dies during participation in the study, the Investigator will provide the
Sponsor with a copy of any post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The Investigator will submit any updated serious TEAE data to the Sponsor within
24 hours of receipt of the information.
Reporting of Serious Treatment-emergent adverse event 
Serious Treatment-Emergent Adverse Event Reporting Via Paper Serious 
Treatment-Emergent Adverse Event Report Form 
•
Facsimile transmission of the Serious Treatment-Emergent Adverse Event Report 
Form (see Figure 2) is the preferred method to transmit this information.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the Serious Treatment-Emergent Adverse 
Event Report Form sent by overnight mail or courier service.
•
Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the Serious Treatment-Emergent Adverse Event Report Form 
within the designated reporting time frames.
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Figure 2.  Sample Serious Treatment-Emergent Adverse Event Report Form  
 
 
     
svc-ags-in-cn@amgen.comsvc-ags-in-cn@amgen.comsvc-ags-in-cn@amgen.com 
1. SITE INFORMATION 
Site Number 
Investigator 
 
Country 
Date of Report 
Day          Month           Year 
 
 
 
 
 
 
 
Reporter 
 
 
Phone Number 
(              ) 
Fax Number 
(              ) 
2. SUBJECT INFORMATION 
Subject ID Number 
Age at event onset  
 
 
Sex 
❑F  ❑M 
Race 
 
If applicable, provide 
End of Study date   
 
 
 
 
 
 
 
 
 
 
 
3. SERIOUS TREATMENT-EMERGENT ADVERSE EVENT - Information in this section must also be entered 
on the Serious Treatment-emergent adverse event Summary CRF 
Provide the date the Investigator became aware of this Serious Treatment-emergent adverse event Information:   
Day_____Month____Year______ 
Serious Treatment-emergent adverse event Diagnosis 
or Syndrome  
If diagnosis is unknown, enter Signs / Symptoms 
When Final Diagnosis is known, enter as Treatment-
emergent adverse event 
 
List one event per line. If event is fatal, enter the Cause of 
Death.  Entry of “Death” is not acceptable, as this is an 
outcome. 
Date 
Started Date Ended 
Ch
ec
k 
on
ly 
if 
ev
en
t 
oc
-
cu
rre
d 
be
for
e 
fir
st 
do
se 
of 
IP 
Enter 
Serious 
Criteria 
code 
 
(see 
codes 
below) 
Relationship 
Is there a reasonable possibility that the event  
may have been caused by IP or an Amgen device used to administer 
the IP?  
 
If yes see section 10 
Out
co
me 
of 
Eve
nt 
 
01
 
Res
olve
d 
02
 
Not 
reso
lved 
03
 
Fat
al 
04 
Unk
now
n 
Check 
only if 
event 
is 
relate
d to  
study 
proce- 
dure  
eg,  
biopsy 
AMG8
0 
IP/device 
IP/device IP/device 
IP/device 
Day     
Month   
Year 
Day     
Month     
Year 
N
o
✓ 
Yes✓ No✓ 
Yes✓ 
No✓ 
Yes✓ 
No✓ 
Yes✓ 
No✓ 
Yes✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Serious 
Criteria: 
01 Fatal 
02 Immediately life- threatening 
03 
Required 
hospitaliz
ation 
04 
Prolonged 
hospitaliz
ation 
05 Persistent or significant disability /incapacity 
06 Congenital anomaly / birth defect 
07 Other 
medically 
important 
serious event 
4. HOSPITALIZATION 
 
Date Admitted 
Date Discharged 
Day       Month       Year 
Day       Month       Year 
Was subject hospitalized or was a hospitalization 
prolonged due to this event? ❑No  ❑Yes, If yes, 
please complete date(s):  
 
 
5. INVESTIGATIONAL PRODUCT (IP) 
 
Initial 
Start 
Date 
Prior to, or at time of Event 
Action Taken with Product 
 
01 Still being Administered 
02 Permanently discontinued 
03 Withheld 
Lot  and 
Serial  
Day    
Month  
Year 
Date 
of 
Dos
e 
Dose 
Route 
Frequency 
Day 
Mon
th   
Yea
r 
AMG890 Open Label 
 
 
 
 
 
 
Lot  
______
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Site Number 
Subject ID Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. CONCOMITANT MEDICATIONS (e.g., chemotherapy)        Any Concomitant Medications?   No  Yes,  
If yes, please complete: 
Medication Name(s) 
Start Date 
Stop Date 
Co-suspect 
Continuing 
Dose 
Route 
Freq. 
Treatment 
Med 
Day        Month        
Year 
Day        Month        
Year 
No✓ Yes✓ No✓ Yes✓ 
No✓ 
Yes✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.  RELEVANT MEDICAL HISTORY (include dates, allergies and any relevant prior therapy) 
 
 
 
 
 
 
 
 
8.  RELEVANT LABORATORY VALUES (include baseline values)  Any Relevant Laboratory values? □ 
No  □ Yes,  If yes, please complete: 
Date 
Test 
 
 
 
 
 
 
 
 
 
 
 
Unit 
 
 
 
 
 
 
 
 
 
 
 
Day            Month            
Year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.  OTHER RELEVANT TESTS (diagnostics and procedures)                Any Other Relevant tests? □ No   
□ Yes,  If yes, please complete: 
Date 
Additional Tests 
Results 
Units 
Day        Month        Year 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Site Number 
Subject ID Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.  CASE DESCRIPTION (Provide narrative details of events listed in section 3) For each event in 
section 3, where relationshipYes, please provide rationale. 
 
 
 
 
 
 
 
Signature of Investigator or Designee 
 
 
 
 
_____________________________________________________ 
I confirm by signing this report that the information on this form, including 
seriousness and causality assessments, is being provided to Amgen by the 
Investigator for this study, or by a Qualified Medical Person authorized by the 
Investigator for this study. 
Title 
Date 
 
 
 
 
 
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Appendix 2.  Clinical Laboratory Evaluations 
Table 3.  Safety Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen or urea 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Direct bilirubina  
Gamma-glutamyl transferase 
Glucose (fasting) 
Indirect bilirubina 
Inorganic phosphate 
Lactateh 
Magnesium 
Phosphorous 
Potassium  
Sodium  
Total bilirubina 
Total cholesterol 
Total CO2 (measured as: 
bicarbonate) 
Total creatine kinase  
Total protein 
Tryptaseg 
Uric acid 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin- 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Bilirubin 
Blood 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination (if 
protein, leukocyte esterase, 
nitrite, or blood is positive) 
Hormone panel - females 
only: 
Follicle-stimulating hormoneb  
(postmenopausal females 
only) 
Serum pregnancy test 
(human chorionic 
gonadotropin)d 
Urine pregnancy testd 
Page 1 of 2 
Footnotes defined on last page of the table 
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Table 3.  Safety Laboratory Evaluations 
Serologyb: 
Drug screenc: 
Other Tests: 
Anti-hepatitis B surface 
antibody 
Anti-hepatitis B core antibody  
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
virus antibodies  
Including, but not limited to:  
Amphetamines/methampheta
mines 
Barbiturates 
Benzodiazepines 
Cocaine 
Methadone 
Phencyclidine 
Opiates 
K2 (Synthetic cannabinoids) 
Tricyclic antidepressants  
Cotinine test 
Alcohol urine test 
Estimated glomerular filtration 
rate (eGFR) b, f 
 
 
 
Coagulation Panel: 
International normalized ratio 
(INR)e  
Prothrombin time (PT) 
Activated partial 
thromboplastin time (APTT) 
 
a Direct and indirect bilirubin will be analyzed if total bilirubin is elevated. 
b Only analyzed at Screening. 
c Only analyzed at Screening and Check-in.  
d Performed in serum at Screening and in urine at all other times for all females. A positive urine pregnancy test will 
be confirmed with a serum pregnancy test. 
e International normalized ratio will be tested if hepatotoxicity is suspected guidelines presented in 
Appendix 7 
f Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease (MDRD) equation. 
g Tryptase to be collected in the case of a suspected anaphylactic reaction. To be performed at the discretion of the 
Investigator or qualified designee.  
h Lactate to be collected if an anion-gap acidosis is identified. To be performed at the discretion of the Investigator or 
qualified designee.  
Table 4.  Pharmacodynamic Laboratory Evaluations 
Lipid panel: 
Additional test: 
Triglycerides a, b 
Very low-density lipoprotein cholesterol 
(VLDL-C) b  
Low-density lipoprotein cholesterol (LDL-C) b 
High-density lipoprotein cholesterol (HDL-C) b 
Total Cholesterol b 
Apolipoprotein A1 (Apo A1) b 
Total Apolipoprotein B (Apo B) b 
Lipoprotein(a) (Lp[a]) c 
a Only analyzed at Screening. 
b After screening, on-study lipids will include triglycerides, VLDL-C, LDL-C, HDL-C, total cholesterol, Apo A1, and 
total Apo B. 
c Part 1 and Part 2 screening, and on study serum Lp(a) samples will be analyzed by a Sponsor-designated 
laboratory. 
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Appendix 3.  Approximate Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
Test 
Volume per blood 
sample (mL) 
Maximum number 
of blood samples 
Total amount of 
blood (mL) 
Clinical Chemistry and 
Hematology 
12 
12 
144 
Coagulation 
3 
9 
27 
Serum Pregnancya 
5 
1 
5 
FSHb 
5 
1 
5 
Serology 
9 
1 
9 
PK 
4 
17 
68 
PD: Lp(a)  
5 
14 
70 
PD: lipid panel 
8.5 
7 
59.5 
Anti-Olpasiran Antibody 
4 
3 
12 
Total: 
399.5 
Abbreviations:  FSH  follicle-stimulating hormone; PK  pharmacokinetic(s); PD  pharmacodynamics(s). 
Note:  
a For female subjects only. A highly sensitive serum pregnancy test should be completed at screening for 
all female subjects. A urine pregnancy test should be completed at all other times. A serum pregnancy 
test will only be performed when the urine pregnancy test is positive.  
b For postmenopausal female subjects only. 
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Appendix 4.  Contraception Requirements 
All subjects must receive pregnancy prevention counseling and be advised of the risk to the 
fetus if they conceive a child during treatment and for 90 days after the dose of Olpasiran. 
Additional medications given during the study may alter the contraceptive requirements. The 
Investigator must discuss these contraceptive changes with the subject. 
Definitions  
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche.  
Women of Non-childbearing Potential: 
1. Surgically sterile: females who are permanently sterile via hysterectomy, bilateral 
salpingectomy, and/or bilateral oophorectomy by reported medical history and/or medical 
records. Surgical sterilization to have occurred a minimum of 6 weeks, or at the 
Investigator’s discretion, prior to Screening.  
2. Postmenopausal: Females with age of  55 years with no menses for at least 12 months; 
or with age of  55 years with no menses for at least 12 months AND with a follicle 
stimulating hormone (FSH) level  40 IU/L or according to the definition of “postmenopausal 
range” for the laboratory involved. The amenorrhea should not be induced by a medical 
condition such as anorexia nervosa, hypothyroid disease or polycystic ovarian disease, or 
by extreme exercise. It should not be due to concomitant medications that may have 
induced the amenorrhea such as oral contraceptives, hormones, gonadotropin-releasing 
hormones, anti-estrogens, or selective estrogen receptor modulators.  
Fertile male: a male that is considered fertile after puberty.  
Infertile male: permanently sterile male via bilateral orchiectomy.  
Contraception Requirements 
Male Subjects: 
Male subjects (even with a history of vasectomy) with partners of childbearing potential must 
use a male barrier method of contraception (i.e., male condom with spermicide) in addition to a 
second method of acceptable contraception by female partner from Check-in until 90 days after 
Olpasiran dosing. Acceptable methods of contraception for female partners include: 
 
hormonal injection 
 
combined oral contraceptive pill or progestin/progestogen-only pill 
 
combined hormonal patch 
 
combined hormonal vaginal ring 
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 
surgical method (bilateral tubal ligation or regulatory approved method of hysteroscopic 
bilateral tubal occlusion) 
 
hormonal implant 
 
hormonal or non-hormonal intrauterine device 
 
over-the-counter sponge with spermicide 
 
cervical cap with spermicide 
 
diaphragm with spermicide. 
Male subjects are required to refrain from donation of sperm from Check-in until 90 days after 
Olpasiran dosing. 
Sexual Abstinence  
Subjects who practice true abstinence, because of the subject’s lifestyle choice (i.e., the subject 
should not become abstinent just for the purpose of study participation), are exempt from 
contraceptive requirements. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post 
ovulation methods) and withdrawal are not acceptable methods of contraception. 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months prior 
to Screening and must agree to remain abstinent from the time of signing the Informed Consent 
Form (ICF) until 90 days after Olpasiran dosing. 
Same-sex Relationships 
For subjects who are exclusively in same-sex relationships, contraceptive requirements do not 
apply. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
Olpasiran dosing. 
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Appendix 5.  Collection of Pregnancy and Lactation Information 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies until 90 days after Olpasiran dosing 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 3). The 
form must be submitted to Amgen Global Patient Safety within 24 hours of learning of a 
subject’s pregnancy. (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 
After obtaining the female subject’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through 90 days after 
Olpasiran dosing. This information will be forwarded to Amgen Global Patient Safety. 
Generally, infant Follow-up will be conducted up to 12 months after the birth of the child 
(if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be a treatment-emergent adverse event 
(TEAE) or serious TEAE, any pregnancy complication or report of a congenital anomaly 
or developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as a TEAE or serious TEAE. Note that an elective termination with no 
information on a fetal congenital malformation or maternal complication is generally not 
considered a TEAE, but still must be reported to the Sponsor as a pregnancy exposure 
case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious TEAE (e.g., female subject experiences a spontaneous abortion, stillbirth, or 
neonatal death or there is a fetal or neonatal congenital anomaly) the Investigator will 
report the event as a serious TEAE. 
 
Any serious TEAE occurring as a result of a poststudy pregnancy which is considered 
reasonably related to the study treatment by the Investigator will be reported to Amgen 
Global Patient Safety as described in Appendix 1. While the Investigator is not obligated 
to actively seek this information in former study subjects, he or she may learn of a 
serious TEAE through spontaneous reporting. 
Male Subjects with Partners Who Become Pregnant or Were Pregnant at the Time of 
Enrollment 
 
In the event a male subject fathers a child during treatment, and for an additional 
90 days after Olpasiran dosing, the information will be recorded on the Pregnancy 
Notification Form. The form (see Figure 3) must be submitted to Amgen Global Patient 
Safety within 24 hours of the site’s awareness of the pregnancy. (Note: Sites are not 
required to provide any information on the Pregnancy Notification Form that violates the 
country or regions local privacy laws). 
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 
The Investigator will attempt to obtain a signed authorization for release of pregnancy 
and infant health information directly from the pregnant female partner to obtain 
additional pregnancy information. 
 
After obtaining the female partner’s signed authorization for release of pregnancy and 
infant health information, the Investigator will collect pregnancy outcome and infant 
health information on the pregnant partner and her baby and complete the pregnancy 
questionnaires. This information will be forwarded to Amgen Global Patient Safety. 
 
Generally, infant Follow-up will be conducted up to 12 months after the birth of the child 
(if applicable). 
 
Any termination of the pregnancy will be reported to Amgen Global Patient Safety 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through 90 days after Olpasiran dosing. 
 
Information will be recorded on the Lactation Notification Form (Figure 4) and submitted 
to Amgen Global Patient Safety within 24 hours of the Investigator’s knowledge of event. 
With the female subject’s signed authorization for release of mother and infant health 
information, the Investigator will collect mother and infant health information and complete the 
lactation questionnaire on any female subject who breastfeeds while taking protocol-required 
therapies through 90 days after the dose of Olpasiran. 
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Figure 3.  Pregnancy Notification Form 
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Figure 4.  Lactation Notification Form 
 
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Appendix 6.  Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines. 
 
Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
 
Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, and 
other relevant documents (e.g., advertisements) must be submitted to an Ethics Committee 
(EC) by the Investigator and reviewed and approved by the EC before the study is initiated. 
Any substantial protocol amendments, likely to affect the safety of the subjects or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study subjects or any non-substantial changes, as defined by 
regulatory requirements. 
The Investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
EC. 
 
Notifying the EC of serious treatment-emergent adverse events (TEAEs) or other 
significant safety findings as required by EC procedures. 
 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other applicable 
local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
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Informed Consent 
An initial sample ICF will be provided for the Investigator (or designee) to prepare the informed 
consent document to be used at his or her site. Updates to the sample ICF are to be 
communicated formally in writing from the Study Manager to the Investigator. The written ICF is 
to be prepared in the language(s) of the potential study participant population. 
The Investigator or his/her delegated representative will explain to the subject, or his/her legally 
authorized representative, the aims, methods, anticipated benefits, and potential hazards of the 
study before any protocol specific screening procedures or any investigational product(s) is/are 
administered and answer all questions regarding the study. 
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative (defined as an individual or other body authorized under applicable 
law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical 
study) will then be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50, local regulations, ICH guidelines, and the EC or study site. 
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her notification 
of the primary care physician is to be documented in the subject’s medical records, and the ICF 
is to be signed and personally dated by the subject or a legally acceptable representative and 
by the person who conducted the informed consent discussion. Subject withdrawal of consent 
or discontinuation from study treatment and/or procedures must also be documented in the 
subject’s medical records. 
Subjects must be re-consented to the most current version of the ICF during their participation 
in the study. 
The original signed ICF is to be retained in accordance with institutional policy, and a copy of 
the ICF must be provided to the subject or the subject’s legally authorized representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the Investigator must provide an impartial witness to read the ICF to the subject 
and must allow for questions. Thereafter, both the subject and the witness must sign the ICF to 
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attest that informed consent was freely given and understood. (Refer to ICH GCP guideline, 
Section 4.8.9.) 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs within 
40 days from the previous ICF signature date. 
Subject Data Protection 
The Investigator must ensure that the subject’s confidentiality is maintained for documents 
submitted to the Sponsor. 
Subjects will be assigned a unique subject number by the site. Any subject records or datasets 
that are transferred to the Sponsor will contain the unique subject number only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the electronic Case Report Form (eCRF) demographics page, in addition to the unique 
subject number, include the age at time of enrollment. 
For serious TEAEs reported to the Amgen, subjects are to be identified by their unique subject 
number (for faxed reports, in accordance with local laws and regulations). 
Documents that are not submitted to the Amgen (e.g., signed ICFs) are to be kept in confidence 
by the Investigator, except as described below. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution permit 
authorized representatives of the company, of the regulatory agency(s), and the EC 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. 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential information of the 
Sponsor, Amgen Inc. The Investigator (or designee) agrees not to disclose such information in 
any way without prior written permission from the Sponsor. The information in this document 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written permission from the Sponsor. 
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Data Quality Assurance 
The following data quality steps will be implemented: 
 
All relevant subject data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. 
 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
 
The Investigator must permit study-related monitoring, audits, EC review, and regulatory 
agency inspections and provide direct access to source data documents. 
 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. Predefined agreed risks, monitoring thresholds, quality 
tolerance thresholds, controls, and mitigation plans will be documented in a risk 
management register. Additional details of quality checking to be performed on the data 
may be included in a Data Management Plan. 
 
A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in the study site archive for 15 years after the end of 
the study unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor. 
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR Part 11 compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion. 
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All data generated from external sources (e.g., laboratory and bioanalytical data), and 
transmitted to the Sponsor or designee electronically, will be integrated with the subject’s eCRF 
data in accordance with the Data Management Plan. 
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An eCRF must be completed for each enrolled subject who undergoes any screening 
procedures, according to the eCRF completion instructions. The Sponsor, or Contract Research 
Organization, will review the supporting source documentation against the data entered into the 
eCRFs to verify the accuracy of the electronic data. The Investigator will ensure that corrections 
are made to the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the data 
on the eCRF, data queries, and site notifications. 
Publications 
The policy for publication of data obtained during this study will be documented in the Clinical 
Study Agreement. 
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Appendix 7.  Hepatotoxicity: Suggested Actions and Follow-up Assessments  
Subjects with normal hepatic function at Screening who experience aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) elevations  3 x upper limit of normal (ULN) or 
subjects with elevated values before drug exposure who have a 2-fold increase above baseline 
values (as specified in the Guidance for Industry Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation, July 2009)32 are to undergo clinical assessments and a period of “close 
observation” until abnormalities return to normal or to the subject’s baseline level as described 
below. 
Clinical Assessments and Observation 
Assessments that are to be performed during this period include: 
 
Repeat AST, ALT, alkaline phosphatase, bilirubin (total and direct), and international 
normalized ratio (INR) within 24 hours  
 
In cases of total bilirubin (TBL)  2  ULN or INR  1.5, retesting of liver tests, bilirubin 
(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. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL. The 
following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin G, anti-nuclear antibody anti-smooth muscle antibody, and 
liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, hypersensitivity 
type reactions, fatigue, nausea, vomiting, and fever 
o Prior and/or concurrent use of alcohol, recreational drugs, and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase, and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
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 
Appropriate blood sampling for PK analysis if this has not already been collected 
 
Hepatology consult (liver biopsy may be considered in consultation with a hepatologist). 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or are considered stable by the Investigator. The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation of 
Olpasiran. 
The potential drug-induced liver injury (DILI) event and additional information such as medical 
history, concomitant medications, and laboratory results must be captured in the corresponding 
electronic Case Report Forms (eCRFs). 
Important alternative causes for elevated AST/ALT and/or TBL values include, but are not 
limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (e.g., 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 (e.g., Gilbert’s syndrome, Crigler 
Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (e.g., indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (e.g., rhabdomyolysis, hemolysis). 
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Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, i.e., cases of AST or ALT  3  ULN and 
concurrent TBL  2  ULN or INR  1.5 (for subjects not on anticoagulation therapy) without 
evidence of alternative cause of the elevations, the following is required: 
 
The event is to be reported to the Sponsor as a serious treatment-emergent adverse 
event (TEAE) within 24 hours of discovery or notification of the event (i.e., before 
additional etiologic investigations have been concluded) 
 
The appropriate eCRF (e.g., Event eCRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities is to be completed and 
sent to the Sponsor. 
Other events of hepatotoxicity and potential DILI are to be reported as serious TEAEs if they 
meet the criteria for a serious TEAE defined in Appendix 1. 
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Appendix 8.  Sample Storage and Destruction  
Any blood sample collected according to the Schedule of Assessments can be analyzed for any 
of the tests outlined in the protocol and for any tests necessary to minimize risks to study 
subjects. This includes testing to ensure analytical methods produce reliable and valid data 
throughout the course of the study. This can also include, but is not limited to, investigation of 
unexpected results, incurred sample reanalysis, and analyses for method transfer and 
comparability. 
 
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Appendix 9.  Schedule of Assessments 
Table 5.  Schedule of Assessments 
PROCEDURE 
Screening Check-in 
Treatment Period 
Study Day 
-40 to -2 
-1 
1 
2 
3 
4 
Study Time (Hours) 
 
 
Predose 
0 
1 
2 
3 
6 
9 
12 
24 
36 
48 
72 
Study Time (Minutes) 
 
 
 
0 
30 
60 
120 180 360 
540 
720 
 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-house Residencya 
 
 
Physical Examinationb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medical History 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGd 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
Vital Signse 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
TEAEsf 
 
 
 
 
Serious TEAEsf 
 
Concomitant Therapy Reviewg 
 
LABORATORY ASSESSMENTS 
Pregnancy Testh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Panel 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Chemistry & Hematologyi, o 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinary Drug Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Urine Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eGFRj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSHk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-Olpasiran Antibody 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC ASSESSMENTS 
Olpasiran Serum PK Collectionl 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PHARMACODYNAMIC ASSESSMENTS 
Lp(a)m 
X 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Lipid Paneln, o 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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PROCEDURE 
Screening Check-in 
Treatment Period 
Study Day 
-40 to -2 
-1 
1 
2 
3 
4 
Study Time (Hours) 
 
 
Predose 
0 
1 
2 
3 
6 
9 
12 
24 
36 
48 
72 
Study Time (Minutes) 
 
 
 
0 
30 
60 
120 180 360 
540 
720 
 
 
 
 
STUDY TREATMENT 
Olpasiran administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: Apo A1 = apolipoprotein A1; Apo B = apolipoprotein B; ECG = electrocardiogram; eGFR = Estimated glomerular filtration rate; FSH = follicle-
stimulating hormone; HLDL-C = High-density lipoprotein; LDL-C = low-density lipoprotein; Lp(a) = lipoprotein(a); TEAE = treatment-emergent adverse event; 
VLDL-C = very low-density lipoprotein.  
a In-house residency from Day -1 through the completion of all assessments on Day 4. 
b Physical examination to include neurologic examination. 
c Interim medical history only. 
d ECG will be single trace (1 × 10-second tracing), prior to safety blood draws or invasive procedures.  
e Sitting blood pressure, sitting pulse rate, respiratory rate and temperature. Pulse rate and BP will be measured using the same arm for each reading after the 
subject has been resting in the sitting position for at least 5 minutes. 
f TEAEs will be recorded from initiation of study treatment on Day 1 until EOS/ET completion. Serious TEAEs will be recorded from the time the subject signs the 
Informed Consent Form until 30 days after the last dose of study treatment or the EOS (whichever is later). 
g Prior and concomitant medication administration will be recorded beginning at informed consent. Also, all Investigator-approved medications taken by a subject 
within 14 days or 5 half-lives (whichever is longer) before dosing on Day 1 for over-the-counter or prescription medications, and 30 days prior to Check-in for 
herbal medicines (e.g., St. John’s wort), vitamins and dietary supplements (with the exception of those known to affect lipid metabolism, which are excluded), will 
be recorded on the subject’s electronic Case Report Form. 
h Performed in serum at Screening and in urine at all other times for all females. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
i Clinical chemistry (fasted at least 10 hours). 
j eGFR will be calculated using the Modification of Diet in Renal Disease (MDRD) equation. 
k Performed in postmenopausal females only. 
l Blood samples for determination of Olpasiran serum concentrations and PK parameters will be collected: Predose, 30 minutes, 60 minutes, 2, 3, 6, 9, 12, 24, and 
36 hours postdose and on Study Days 3, 4, 7, 15, 29, 57, and 85 following administration of Olpasiran on Day 1. The PK samples collected on Day 1 will have a 
sampling window of ± 10 minutes, postdose samples collected on Day 2 through Day 4 will have a sampling window of ± 1 hour, postdose samples collected on 
Day 7 through Day 57 will have a sampling window of ± 48 hours, and postdose samples collected on Day 85 through EOS will have a sampling window of ± 5 
days. Times of all PK samples will be recorded to the nearest minute.  
m Part 1 and Part 2 screening, and on study serum Lp(a) samples will be analyzed by a Sponsor-designated laboratory.  
n At screening, lipids will measure triglycerides only. After screening, on-study lipids will include triglycerides, VLDL-C, LDL-C, HDL-C, total cholesterol, Apo A1, 
and total Apo B.  
o Subjects will be fasted overnight (at least 10 hours) before collection of blood samples for clinical chemistry evaluations or lipids.  
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Table 6.  Schedule of Assessments 
PROCEDURE 
Treatment Period 
EOS 
Study Day 
7 
15 
29 
57 
85 
113 
155 
183 
211a 
225 
Study Time (Hours) 
144 
 
 
 
 
 
 
 
 
 
GENERAL AND SAFETY ASSESSMENTS 
 
 
 
Physical Examinationb  
 
 
X 
 
X 
 
X 
 
 
X 
Weight 
 
 
 
 
 
 
 
 
 
X 
ECGc 
 
X 
X 
 
X 
 
X 
 
 
X 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Therapies Reviewf 
 
 
 
 
TEAEse 
 
 
 
 
Serious TEAEse 
 
 
 
 
Telephone Visita 
 
 
 
 
 
 
 
 
X 
 
LABORATORY ASSESSMENTS 
 
 
 
Pregnancy Testg 
 
 
 
 
 
 
 
 
 
X 
Coagulation Panel 
 
X 
 
X 
 
X 
X 
X 
 
 
Chemistry & Hematologyh, l 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis 
 
 
X 
 
 
 
 
 
 
X 
Anti-Olpasiran Antibody  
 
 
X 
 
 
 
 
 
 
X 
PHARMACOKINETIC ASSESSMENTS 
 
 
 
Olpasiran Serum PK Collectioni 
X 
X 
X 
X 
X 
 
 
 
 
 
PHARMACODYNAMIC ASSESSMENTS 
 
 
 
Lp(a)j 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Lipid Panelk, l 
X 
X 
 
X 
 
 
X 
 
 
X 
Abbreviations: Apo A1 = apolipoprotein A1; Apo B = apolipoprotein B; ECG = electrocardiogram; EOS = end of study; HLDL-C = High-density lipoprotein; LDL-C = 
low-density lipoprotein; Lp(a) = lipoprotein(a); TEAE = treatment-emergent adverse event; VLDL-C = very low-density lipoprotein.  
a A telephone visit will be scheduled for TEAE assessments on Day 211 with a visit window of ± 3 days. Subjects will be brought in only based on any safety 
concern(s) identified by the investigator.  
b Physical examination to include neurologic examination. 
c ECG will be single trace (1 × 10-second tracing), prior to safety blood draws or invasive procedures.  
d Sitting blood pressure, sitting pulse rate, respiratory rate and temperature. Pulse rate and BP will be measured using the same arm for each reading after the 
subject has been resting in the sitting position for at least 5 minutes. 
e TEAEs will be recorded from initiation of study treatment on Day 1 until EOS/ET completion. Serious TEAEs will be recorded from the time the subject signs the 
Informed Consent Form until 30 days after the last dose of study treatment or the EOS (whichever is later). 
f Prior and concomitant medication administration will be recorded beginning at informed consent. Also, all Investigator-approved medications taken by a subject 
within 14 days or 5 half-lives (whichever is longer) before dosing on Day 1 for over-the-counter or prescription medications, and 30 days prior to Check-in for 
herbal medicines (e.g., St. John’s wort), vitamins and dietary supplements (with the exception of those known to affect lipid metabolism, which are excluded), will 
be recorded on the subject’s electronic Case Report Form. 
g Performed in serum at Screening and in urine at all other times for all females. A positive urine pregnancy test will be confirmed with a serum pregnancy test. 
h Clinical chemistry (fasted at least 10 hours). 
Page 83 of 266


Protocol 
CONFIDENTIAL 
Labcorp Study: 8424665AMGEN Protocol Reference: 20190095 
Protocol Version 3.0, 28 July 2021 Page 79 of 79 
i Blood samples for determination of Olpasiran serum concentrations and PK parameters will be collected at the following timepoints: predose, 30 minutes, 60 
minutes, 2, 3, 6, 9, 12, 24, and 36 hours postdose and on Study Days 3, 4, 7, 15, 29, 57, and 85 following administration of Olpasiran on Day 1. The PK samples 
collected on Day 1 will have a sampling window of ± 10 minutes, postdose samples collected on Day 2 through Day 4 will have a sampling window of ± 1 hour, 
postdose samples collected on Day 7 through Day 57 will have a sampling window of ± 48 hours, and postdose samples collected on Day 85 through EOS will 
have a sampling window of ± 5 days. Times of all PK samples will be recorded to the nearest minute.  
j Part 1 and Part 2 screening, and on study serum Lp(a) samples will be analyzed by a Sponsor-designated laboratory. 
k At screening, lipids will measure triglycerides only. After screening, on-study lipids will include triglycerides, VLDL-C, LDL-C, HDL-C, total cholesterol, Apo A1, 
and total Apo B. 
l Subjects will be fasted overnight (at least 10 hours) before collection of blood samples for clinical chemistry evaluations or lipids. 
 
Page 84 of 266


Protocol Amendment Summary 
CONFIDENTIAL 
Labcorp Study: 8424665 
Amgen Protocol Reference: 20190095 
Protocol Version 3.0, 28 July 2021 
Page 1 of 3 
Summary of Amended Protocol Changes 
An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety and Tolerability of Olpasiran in Chinese Subjects 
With Elevated Serum Lipoprotein(a)  
Protocol Version 1.0 Date: 09 October 2020 
Protocol Version 2.0 Date: 03 May 2021 
Protocol Version 3.0 Date: 28 July 2021 
Protocol Version 3.0 Status: Final 
 
Investigational Medicinal Product:  Olpasiran (AMG 890) 
 
Amgen Protocol Reference Number: 20190095 
Labcorp Study Number: 8424665 
 
 
 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the 
express written permission of the Sponsor. 
Page 2 of 266


Protocol Amendment Summary 
CONFIDENTIAL 
Labcorp Study: 8424665 
Amgen Protocol Reference: 20190095 
Protocol Version 3.0, 28 July 2021 
Page 2 of 3 
Protocol Version 2.0 (dated 03 May 2021) has been amended to implement the 
following changes:  
1. The name of the Contract Research Organization (CRO) was updated to 
reflect the current official legal name. 
2. The names and contact information for the Sponsor’s Study Manager and 
CRO Project Manager have been updated in the Study Identification section. 
3. Section 4.1, Inclusion Criteria, was updated to clarify that subject eligibility 
based on lipoprotein(a) (Lp[a]) levels is determined by the results from Part 1 
of the screening period. 
4. Section 4.2, Exclusion Criteria, was updated to allow investigator discretion in 
consultation with the study medical monitor in determining eligibility for 
subjects with prothrombin time (PT) and/or activated partial thromboplastin 
time (APTT) values that are outside of the laboratory’s normal reference 
range at screening. 
5. Section 4.2, Exclusion Criteria, was updated to correct the fasting glucose unit 
from nmol/L to mmol/L for Exclusion Criterion 4.  
Minor changes: 
1. The protocol version and date were updated throughout the protocol. 
2. Typographical errors and formatting errors were corrected, as necessary. 
3. Definitions of PT and APTT were added in the abbreviation list.  
A detailed summary of changes is presented below: 
Study Identification 
Now reads: 
Sponsor’s Study Manager 
 
Global Early Clinical Development Manager 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Tel: 
  
Email: 
 
Page 3 of 266


Protocol Amendment Summary 
CONFIDENTIAL 
Labcorp Study: 8424665 
Amgen Protocol Reference: 20190095 
Protocol Version 3.0, 28 July 2021 
Page 3 of 3 
Labcorp Project Manager 
  
Senior Project Manager 
Labcorp Clinical Pharmacology Services  
USA 
Tel:
Email: 
 
Section 4.1 Inclusion Criteria 
Now reads: 
Inclusion eligibility criteria will be evaluated in 2 parts during the screening period: 
 Part 1: After written informed consent is obtained, subjects will provide a 
blood sample for a preliminary Lp(a) assessment to determine eligibility for 
Part 2 screening. Subjects with Lp(a)  70 nmol/L (or approximately 
 27 mg/dL) will be eligible to return to the CRU for Part 2 screening. Subjects 
not eligible to return for Part 2 screening will be screen failed. 
 Part 2: Eligible subjects will complete all remaining screening procedures and 
tests that establish eligibility within 40 days prior to the Day 1 visit.  
Section 4.2 Exclusion Criteria 
Now reads: 
4. History or clinical evidence of bleeding diathesis or any coagulation disorder, 
including prothrombin time (PT), activated partial thromboplastin time (APTT), 
or platelet count outside of the laboratory’s normal reference range at 
screening. Subjects with PT and/or APTT values that are outside of the 
laboratory’s normal reference range at screening may still be eligible to 
proceed to enrollment if the results are judged by the investigator in 
consultation with the study medical monitor to not be clinically significant. 
5. History or clinical evidence of diabetes mellitus, including a fasting glucose 
 125 mg/dL (6.9 mmol/L) at Screening. 
 
 
Sponsor approval of these changes is indicated by the signatures in the complete 
amended document, Protocol Version 3.0 for study 20190095. 
Page 4 of 266


Page 1 of 22 
 
Protocol Amendment 1.0 
Summary of Changes 
Title:  An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Olpasiran 
in Chinese Subjects With Elevated Serum Lipoprotein(a) 
Sponsor： Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
No. 
Page, 
Original 
Amendment 
Rationale 
1 
 
Title page, 
Investigator 
agreement 
page 
An Open-label, Single-dose Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics, 
Safety and Tolerability of AMG 890 in Chinese 
Subjects With Elevated Serum Lipoprotein(a) 
 
An Open-label, Single-dose Study to Evaluate 
the Pharmacokinetics, Pharmacodynamics, 
Safety and Tolerability of AMG 890Olpasiran 
in Chinese Subjects With Elevated Serum 
Lipoprotein(a) 
 
Updated 
product name 
in the study 
title and 
through the 
protocol. 
2 
 
Title page 
Protocol Date: 09 October 2020 
Protocol Version: 1.0 
Investigational Product: AMG 890 
 
Protocol Date: 09 October 202003 May 2021 
Protocol Version: 12.0 
Investigational Product: Olpasiran (AMG 890) 
 
Updated 
protocol date 
and version. 
Updated 
product name.  
3 
 
Page footer 
Protocol Version 1.0, 09 October 2020 
Protocol Version 12.0, 09 October 202003 May 
2021 
Updated 
protocol date 
and version. 
4 
 
Throughout 
the whole 
protocol 
AMG 890 
AMG 890Olpasiran 
 
Updated 
product name 
through the 
protocol.  
Page 86 of 266


Page 2 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
5 
 
Throughout 
the whole 
protocol 
eg 
eg,e.g. 
Editorial 
revision. 
6 
 
Throughout 
the whole 
protocol 
ie 
ie,i.e. 
Editorial 
revision. 
7 
 
5 
This will be an open-label, randomized, single-
dose parallel group study in Chinese subjects with 
elevated serum Lp(a). Potential subjects will be 
screened within 28 days prior to the dose. 
This will be an open-label, randomized, single-
dose parallel group study in Chinese subjects with 
elevated serum Lp(a). Potential subjects will be 
screened within 2840 days prior to the dose.  
Updated 
screening 
period to 40 
days.  
8 
 
5 
Group B  
 mg administered as
 
(
 mg/mL) SC injections 
Group B  
 mg administered as
mL (
 mg/mL) SC injections 
Corrected the 
errors of 
Dosage Level 
of Olpasiran 
(Group B; 
number and 
volume of SC 
injections) for 
consistency 
with the 
Investigational 
Product 
Preparation 
and 
Administratio
n (IPPA) 
document. 
9 
 
5 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 
weeks. 
Planned study duration (Screening to EOS): 
approximately 36 weeks. 
Duration of subject participation in the study: 
Planned Screening duration: approximately 46 
weeks. 
Planned study duration (Screening to EOS): 
approximately 3638 weeks. 
Updated 
screening 
period to 40 
days and 
therefore also 
updated the 
Page 87 of 266


Page 3 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
study 
duration. 
10  
14 
Currently, AMG 890 is being studied in two 
phase 1 studies in healthy subjects (first-in-
human [FIH] Study 20170544 and Study 
20180222). The FIH Study 20170544 is a blinded 
study in subjects with elevated plasma Lp(a), 
which is designed to evaluate safety and 
tolerability as primary endpoints, and to address 
PK and pharmacodynamics (PD) effects as 
secondary endpoints. Study 20180222 is an open-
label study in Japanese and non-Japanese subjects 
to characterize AMG 890 PK as the primary 
endpoint and assess safety and tolerability as the 
secondary endpoint. AMG 890 was evaluated at 
dose ranges of  mg to 
 mg in both of these 
phase 1 studies. 
 
Currently, AMG 890Olpasiran is being studied 
in two phase 1 studies in healthy subjects (first-
in-human [FIH] Study 20170544 and Study 
20180222). The FIH Study 20170544 is a 
blindedan ongoing double-blind placebo-
controlled study in healthy subjects with 
elevated plasma Lp(a), which is designed to 
evaluate safety and tolerability as primary 
endpoints, and to address PK and 
pharmacodynamics (PD) effects as secondary 
endpoints. Study 20180222 is ana completed 
open-label study in Japanese and non-Japanese 
subjects to characterize AMG 890Olpasiran PK 
as the primary endpoint and assess safety and 
tolerability as the secondary endpoint. AMG 
890endpoints. Olpasiran was evaluated at dose 
ranges of  mg to 
 mg in both of these phase 1 
studies. 
Updated 
clinical study 
information 
according to 
the latest 
version 4.0 IB.  
11  
15-16 
AMG 890 was well tolerated in the Sprague 
Dawley rat and cynomolgus monkey toxicology 
AMG 890Olpasiran was well tolerated in the 
Sprague DawleyInvestigational New Drug 
Updated 
toxicology 
according to 
Page 88 of 266


Page 4 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
studies.  All dose levels in the monkey toxicology 
studies reduced serum Lp(a) by  90.  In the 
Investigational New Drug (IND)-enabling GLP 
57-day rat and monkey toxicology studies and in 
the registrational GLP 6-month rat and 9-month 
monkey studies, AMG 890 was administered at 
10, 30, and 150 mg/kg once monthly.  In rats at 
10 mg/kg, the only AMG 890 related change was 
minimal to mild accumulation of basophilic 
granular material in the proximal convoluted 
tubular epithelium of the renal cortex in the 6-
month study.  In monkeys at 10 mg/kg, the only 
AMG 890-related changes were Kupffer cell 
hypertrophy/hyperplasia (with cytoplasmic 
vacuolization and basophilia) in the liver and 
vacuolation of macrophages in the subcutis at the 
injection site and in the lymph nodes.  AMG 890 
related changes in the liver, kidneys, lymph 
nodes, and injection site were consistent with 
investigational product uptake, a known N-
acetylgalactosamine (GalNAc) conjugated 
siRNA-related platform effect and not specific to 
AMG 89018,19,20. 
(IND)-enabling (57-day rat and cynomolgus 
monkey) and registrational (6-month rat, 9-
month monkey) GLP toxicology studies.  All 
dose levels in the monkey toxicology studies 
reduced serum Lp(a) by  90.  In the 
Investigational New Drug (IND)--enabling GLP 
57-day rat and monkey toxicology studies and in 
the registrational GLP 6-month rat and 9-month 
monkey studies, AMG 890Olpasiran was 
administered at 10, 30, and 150 mg/kg once 
monthly.  In rats at 10 mg/kg, the only AMG 
890Olpasiran related change was minimal to 
mild accumulation of basophilic granular material 
in the proximal convoluted tubular epithelium of 
the renal cortex in the 6-month study.  In 
monkeys at 10 mg/kg, the only AMG 
890Olpasiran-related changes were Kupffer cell 
hypertrophy/hyperplasia (with cytoplasmic 
vacuolization and basophilia) in the liver and 
vacuolation of macrophages in the subcutis at the 
injection site and in the lymph nodes.  AMG 890 
; the vacuolation of macrophages in the 
subcutis at the injection site was not observed 
the latest 
version 4.0 IB. 
Page 89 of 266


Page 5 of 22 
No. 
Page, 
Original 
Amendment 
Rationale 
There were other AMG 890-related changes that 
occurred either at higher dose levels or a more 
frequent dosing regimen (eg, weekly in the 
exploratory studies) included transient changes in 
cholesterol (rats only), serum alanine 
aminotransferase (ALT), serum alkaline 
phosphatase (ALP), and bilirubin. The only AMG 
890-related finding considered secondary to 
silencing of LPA gene expression was reduction 
in serum Lp(a) in monkeys. 
…… 
In an exploratory embryo fetal development 
toxicology study in the rat, there were no AMG 
890 related mortalities, clinical signs, maternal 
ovarian or uterine abnormalities, or fetal external 
or visceral abnormalities.   
in the 9-month monkey toxicology study. 
Olpasiran-related changes in the liver, kidneys, 
lymph nodes, and injection site were consistent 
with investigational product uptake, a known N-
acetylgalactosamine (GalNAc) conjugated 
siRNA-related platform effect and not specific to 
AMG 890Olpasiran18,19,20. 
There were other AMG 890Olpasiran-related 
changes that occurred either at higher dose levels 
or a more frequent dosing regimen (eg,e.g., 
weekly in the exploratory studies) included 
transient, minimal to mild increases changes in 
cholesterol (rats only), serum alanine 
aminotransferase (ALT), and minimal to mild 
increases in serum alkaline phosphatase (ALP), 
and bilirubin. Additional Olpasiran-related 
changes occurring at higher dose levels or with 
increased frequency of dosing included 
basophilic granules in the proximal tubular 
epithelial cells of the kidney. Olpasiran-related 
liver changes at higher dose levels or increased 
frequency of dosing consisted of hepatocellular 
vacuolation, increased single cell necrosis and 
Page 90 of 266


Page 6 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
mitoses of hepatocytes, and basophilic 
granular material in Kupffer cells in the liver 
in rats and hepatocellular hypertrophy with 
cytoplasmic rarefaction in monkeys. The only 
AMG 890Olpasiran-related finding considered 
secondary to silencing of LPA gene expression 
was a reduction in serum Lp(a) in monkeys. 
…… 
In an exploratory embryo fetal development 
toxicology study in the rat, there were no AMG 
890 Olpasiran-related mortalities, clinical signs, 
maternal ovarian or uterine abnormalities, or fetal 
external or visceral abnormalities. when 
pregnant rats received up to 200 mg/kg 
Olpasiran SC daily on gestation Day (GD) 7 
through GD 17.   
12  
17-18 
Study 20170544 (FIH) 
As of the 19 March 2020 data snapshot date, 
AMG 890 or placebo had been administered to 
64 subjects in Study 20170544; these subjects 
included 40 subjects with screening serum Lp(a) 
 70 to  200 nmol/L in 5 different single doses 
(cohorts 1 to 5:
 mg) and 24 
Study 20170544 (FIH) 
As of the 19 March 2020 data snapshot date, 
AMG 890Olpasiran or placebo had been 
administered to 64 subjects in Study 
20170544;(48 Olpasiran and 16 placebo). Of 
these subjects included 4030 subjects with 
screening serumplasma Lp(a) between  70 to  
Updated 
clinical study 
information 
according to 
the latest 
version 4.0 IB. 
Page 91 of 266


Page 7 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
subjects with screening serum Lp(a)  200 
nmol/L in 2 different single doses (high Lp[a] 
cohorts 6 and 7:  and 
 mg). No AMG 890 
treated subjects in Study 20170544 had a serious 
adverse event (AE). One placebo subject in 
cohort 6 of Study 20170544 had grade 2 serious 
AEs of non-cardiac chest pain and cardiac 
telemetry abnormal on Study Day 128 that 
resolved. There have been no fatal or life-
threatening AEs reported. No clinically relevant 
changes in liver function tests, platelets or 
coagulation parameters, or renal function 
(creatinine) have been detected. Overall, no 
notable trends in AEs, vital signs, or laboratory 
results have been observed to date. As of 
19 March 2020, all 64 subjects enrolled in cohorts 
1 to 7 of Study 20170544 had completed the 
treatment phase of the study. 
……. 
Study 20180222 (Japanese PK) 
…… 
200199 nmol/L inreceived 5 different single 
doses (cohorts 1 to 5: 
 mg) 
and 2418 subjects with screening serumplasma 
Lp(a)  200 nmol/L inreceived 2 different single 
doses (high Lp[a] cohorts 6 and 7:  and 
 mg). 
No AMG 890 treated Two additional cohorts 
were added to Study 20170544 and are 
ongoing (cohort 8 [
 mg] and cohort 9 [
 
mg] included subjects with screening plasma 
Lp(a)  200 nmol/L). As of 19 March 2020, no 
data are available for reporting from cohorts 8 
and 9. All 64 subjects in enrolled in cohorts 1 to 
7 of Study 20170544 had a serious adverse event 
(AE). One placebo subject in cohort 6 of Study 
20170544 had gradehave completed the 
treatment phase of the study (cohorts 1 and 2 
serious AEs of non-cardiac chest pain and cardiac 
telemetry abnormal on Study Day 128 that 
resolved.: Day 113 and cohorts 3 to 7: Day 
225). There have been no fatal or life-threatening 
or fatal adverse events (AEs) reported, and no 
serious AEs reported in subjects treated with 
Olpasiran. No clinically relevant changes in liver 
Page 92 of 266


Page 8 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
AMG 890 was administered to a total of 27 
subjects; 21 subjects in 4 different single doses 
 mg) in Japanese subjects and to 
6 subjects in 1 single dose (
 mg) in non-
Japanese subjects. No fatal, serious, or 
life-threatening AEs were reported. In general, 
AMG 890 was well tolerated at the doses tested. 
To date, all subjects have completed the study. 
function tests, platelets or coagulation parameters, 
or renal function (creatinine) have been detected. 
Overall, no notable trends in AEs, vital signs, or 
laboratory results have been observed to date. As 
of 19 March 2020, all 64 subjects enrolled in 
cohorts 1 to 7 of Study 20170544 had completed 
the treatment phase of the study. 
…… 
Study 20180222 (Japanese PK) 
…… 
AMG 890Olpasiran was administered to a 
total of 27 subjects;: 21 subjects in 4 different 
single doses 
 mg) in Japanese 
subjects and to 6 subjects in 1 single dose (
 
mg) in non-Japanese subjects. No fatal, serious, 
or life-threatening AEs were reported. In general, 
AMG 890 was well tolerated at the doses tested. 
To date, all subjects have completed the 
study.Olpasiran was shown to be safe and well 
tolerated. No patterns indicative of clinically 
important adverse events, laboratory 
abnormalities, or vital sign abnormalities were 
Page 93 of 266


Page 9 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
observed. No serious or fatal adverse events 
were reported from this study.  
Page 94 of 266


Page 10 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
Page 95 of 266


Page 11 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
13  
23-24 
 
Potential subjects will be screened to assess their 
eligibility to enter the study within 28 days prior 
to dose administration. Subjects will be admitted 
into the phase I Clinical Research Unit (CRU) on 
Day -1 and be confined to the CRU until 
discharge on Day 4. Subjects will return to the 
CRU for outpatient visits on Days 7, 15, 29, 57, 
 
 
Potential subjects will be screened to assess their 
eligibility to enter the study within 2840 days 
prior to dose administration. Subjects will be 
admitted into the phase I Clinical Research Unit 
(CRU) on Day -1 and be confined to the CRU 
until discharge on Day 4. Subjects will return to 
Updated 
screening 
period to 40 
days and 
therefore also 
updated the 
total study 
duration. 
Page 96 of 266


Page 12 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
85, 113, 155, and 183, and at the end of study 
(EOS) visit on Day 225. A telephone visit will be 
scheduled for TEAE assessments on Day 211. 
The total duration of study participation for each 
subject (from Screening through EOS visit) is 
anticipated to be approximately 253 days (36 
weeks). 
 
the CRU for outpatient visits on Days 7, 15, 29, 
57, 85, 113, 155, and 183, and at the end of study 
(EOS) visit on Day 225. A telephone visit will be 
scheduled for TEAE assessments on Day 211. 
The total duration of study participation for each 
subject (from Screening through EOS visit) is 
anticipated to be approximately 253265 days 
(36about 38 weeks). 
14  
25 
Part 2: Eligible subjects will complete all 
remaining screening procedures and tests, 
including definitive determination of Lp(a) levels, 
that establish eligibility within 28 days prior to 
the Day 1 visit. 
Part 2: Eligible subjects will complete all 
remaining screening procedures and tests, 
including definitive determination of Lp(a) levels, 
that establish eligibility within 2840 days prior to 
the Day 1 visit. 
Updated 
screening 
period to 40 
days.  
15  
32 
AMG 890 (Group A) 
 mg/mL vialb 
AMG 890 SC injection 
 mg 
) 
SC injection 
AMG 890Olpasiran (Group A) 
 mg/mL vialb 
AMG 890Olpasiran SC injection 
 mg (
) 
SC injection 
Removed 
irrelevant 
information. 
Page 97 of 266


Page 13 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
The amount dispensed, amount returned, 
date/time dispensed, lot number, box 
number of investigational product is to 
be recorded on each subject's CRF(s). 
The Investigator or study physician must 
be available when the subject receives 
the dose of AMG 890 for immediate 
intervention in case of complication(s). 
 
The amount dispensed, amount returned, 
date/time dispensedof administration, lot 
number, box number of investigational 
product is to be recorded on each subject's 
CRF(s). 
The Investigator or study physician must be 
available when the subject receives the dose 
of AMG 890Olpasiran for immediate 
intervention in case of complication(s). 
16  
32 
AMG 890 (Group B) 
 mg/mL vialb 
AMG 890 SC injections 
 mg 
) 
SC injection 
The amount dispensed, amount returned, 
date/time dispensed, lot number, box 
number of investigational product is to 
be recorded on each subject's CRF(s). 
 
. 
The Investigator or study physician must 
be available when the subject receives 
the dose of AMG 890 for immediate 
intervention in case of complication(s). 
 
AMG 890Olpasiran (Group B) 
 mg/mL vialb 
AMG 890Olpasiran SC injections 
 mg (
 
SC injection 
The amount dispensed, amount returned, 
date/time dispensedof administration, lot 
number, box number of investigational product 
is to be recorded on each subject's CRF(s). 
 
 
The Investigator or study physician must be 
available when the subject receives the dose of 
AMG 890Olpasiran for immediate 
intervention in case of complication(s). 
Corrected the 
errors of 
Dosage Level 
of Olpasiran 
(Group B; 
number and 
volume of SC 
injections) for 
consistency 
with the IPPA 
document. 
Removed 
irrelevant 
information. 
17  
32 
a AMG 890 will be manufactured and packaged 
by Amgen and distributed using Amgen clinical 
study drug distribution procedures.  
b Provided as a
 
deliverable volume of 
 mg/mL AMG 890. 
a AMG 890Olpasiran will be manufactured and 
packaged by Amgen and distributed using 
Amgen clinical study drug distribution 
procedures.  
Corrected the 
errors of 
Dosage Level 
of Olpasiran 
(Group B; 
number and 
Page 98 of 266


Page 14 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
 
b Provided as a
 
.maximum deliverable 
volume of 
 
 
will be used to 
administer the 
 mg dose.  
 
volume of SC 
injections) for 
consistency 
with the IPPA 
document. 
18  
35 
Informed consent must be obtained before 
completing any screening procedure or 
discontinuation of standard therapy for any 
disallowed therapy. After the subject has signed 
the ICF, the site will screen the subject to assess 
eligibility for participation. The screening 
window is up to 28 days. 
All screening evaluations must be completed and 
reviewed to confirm that potential subjects meet 
all eligibility criteria. The investigator will 
maintain a screening log to record details of all 
subjects screened and to confirm eligibility or 
record reasons for screening failure, see Section 
4.3 as applicable. 
If a subject has not met all eligibility criteria at 
the end of the screening period, the subject will 
Informed consent must be obtained before 
completing any screening procedure or 
discontinuation of standard therapy for any 
disallowed therapy. After the subject has signed 
the ICF, the site will screen the subject to assess 
eligibility for participation. The screening 
window is up to 2840 days. 
All screening evaluations must be completed and 
reviewed to confirm that potential subjects meet 
all eligibility criteria. The investigator will 
maintain a screening log to record details of all 
subjects screened and to confirm eligibility or 
record reasons for screening failure, see Section 
4.3 as applicable. 
If a subject has not met all eligibility criteria at 
the end of the screening period, the subject will 
Updated the 
screening 
period to 40 
days. 
Page 99 of 266


Page 15 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
be registered as a screen failure. Screen failed 
subjects may be eligible for re-screening 3 times. 
Once the subject is registered as rescreened, a 
new 28-day screening window will begin. 
Subjects will retain the same unique identification 
number assigned at the original screening. If the 
rescreening period begins more than 28 days after 
the original signing of the ICF, all screening 
procedures, including informed consent, must be 
repeated as well. 
Laboratory assessments used to determine subject 
eligibility may be repeated once for confirmation, 
allowing for up to a total of two assessments 
during the 28-day screening period, if necessary, 
before the subject is considered a screen failure. 
If any assessments are repeated during the 
screening period, the value that is closest to the 
enrollment date will apply for the determination 
of eligibility. 
be registered as a screen failure. Screen failed 
subjects may be eligible for re-screening 3 times. 
Once the subject is registered as rescreened, a 
new 2840-day screening window will begin. 
Subjects will retain the same unique identification 
number assigned at the original screening. If the 
rescreening period begins more than 2840 days 
after the original signing of the ICF, all screening 
procedures, including informed consent, must be 
repeated as well. 
Laboratory assessments used to determine subject 
eligibility may be repeated once for confirmation, 
allowing for up to a total of two assessments 
during the 2840-day screening period, if 
necessary, before the subject is considered a 
screen failure. If any assessments are repeated 
during the screening period, the value that is 
closest to the enrollment date will apply for the 
determination of eligibility. 
19  
37 
Venous blood samples (approximately 6 mL) will 
be collected for measurement of Lp(a) at times 
Venous blood samples (approximately 65 mL) 
will be collected for measurement of Lp(a) at 
Updated blood 
volumes for 
Lp(a) and 
lipid panel 
analyses.  
Page 100 of 266


Page 16 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
indicated in the Schedule of Assessments in 
Appendix 9.  
Lipid panel will include triglycerides, VLDL-C, 
LDL-C, and HDL-C, total cholesterol, ApoA1, 
and total Apo B. At Screening, lipids will 
measure triglycerides only. Subjects will be 
fasted overnight (at least 10 hours) before 
collection of blood samples for lipids. Venous 
blood samples (approximately 6 mL) will be 
collected for measurement of lipids at the times 
indicated in the Schedule of Assessments in 
Appendix 9.  
times indicated in the Schedule of Assessments in 
Appendix 9.  
Lipid panel will include triglycerides, VLDL-C, 
LDL-C, and HDL-C, total cholesterol, ApoA1, 
and total Apo B. At Screening, lipids will 
measure triglycerides only. Subjects will be 
fasted overnight (at least 10 hours) before 
collection of blood samples for lipids. Venous 
blood samples (approximately 68.5 mL) will be 
collected for measurement of lipids at the times 
indicated in the Schedule of Assessments in 
Appendix 9.  
20  
41 
Subjects will be asked to provide urine samples 
for drugs of abuse screen and cotinine test, and 
will undergo an alcohol breath test at the times 
indicated in the Schedule of Assessments in 
Appendix 9. For all female subjects, a pregnancy 
test and FSH screen for postmenopausal women 
will be performed at the times indicated in the 
Schedule of Assessments in Appendix 9 
Subjects will be asked to provide urine samples 
for drugs of abuse screen and cotinine test, and 
will undergo an alcohol breathurine test at the 
times indicated in the Schedule of Assessments in 
Appendix 9. For all female subjects, a pregnancy 
test and FSH screen for postmenopausal women 
will be performed at the times indicated in the 
Schedule of Assessments in Appendix 9. 
Switched the 
Alcohol 
Breath Test to 
the Alcohol 
Urine Test due 
to COVID-19 
pandemic at 
screening and 
Check-in 
visits. 
21  
42 
Systolic/diastolic BP, heart rate, respiratory rate, 
and body temperature will be assessed in sitting 
Systolic/diastolic BP, heartpulse rate, respiratory 
rate, and body temperature will be assessed in 
Updated to 
pulse rate per 
Page 101 of 266


Page 17 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
position at the times indicated in the Schedule of 
Assessments in Appendix 9. Heart rate and BP 
will be measured using the same arm for each 
reading after the subject has been resting in the 
sitting position for at least 5 minutes. Vital signs 
may also be performed at other times if judged to 
be clinically appropriate or if the ongoing review 
of the data suggests a more detailed assessment of 
vital signs is required. The position selected for a 
subject should be the same position used 
throughout the study and documented on the vital 
sign CRF. 
All measurements will be performed singly and 
repeated once (within a total of 5 minutes) if 
outside the relevant clinical reference range. 
Subjects must be sitting for at least 5 minutes 
before BP and heart rate measurements. When 
vital signs are scheduled at the same time as 
blood draws, the blood draws will be obtained at 
the scheduled timepoint, and the vitals will be 
obtained as close to the scheduled blood draw as 
sitting position at the times indicated in the 
Schedule of Assessments in Appendix 9. 
HeartPulse rate and BP will be measured using 
the same arm for each reading after the subject 
has been resting in the sitting position for at least 
5 minutes. Vital signs may also be performed at 
other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a 
more detailed assessment of vital signs is 
required. The position selected for a subject 
should be the same position used throughout the 
study and documented on the vital sign CRF. 
All measurements will be performed singly and 
repeated once (within a total of 5 minutes) if 
outside the relevant clinical reference range. 
Subjects must be sitting for at least 5 minutes 
before BP and heartpulse rate measurements. 
When vital signs are scheduled at the same time 
as blood draws, the blood draws will be obtained 
at the scheduled timepoint, and the vitals will be 
obtained as close to the scheduled blood draw as 
site 
requirement.  
Page 102 of 266


Page 18 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
possible, but preferably prior to the safety blood 
draw. 
possible, but preferably prior to the safety blood 
draw. 
22  
45 
Amgen Inc. AMG 890 – Investigator’s Brochure. 
(Version 3.0). 06 November 2019. 
1. Amgen Inc. Olpasiran (AMG 890) – 
Investigator’s Brochure. (Version 34.0). 06 
November 2019January 2021. 
Updated 
reference 
according the 
latest version 
4.0 IB.  
23  
58 
Drug screenc: 
Including, but not limited to:  
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
Tricyclic antidepressants  
Cotinine test 
Alcohol breath test 
 
Drug screenc: 
Including, but not limited to:  
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
cannabinoids 
K2 (Synthetic cannabinoids)  
Tricyclic antidepressants  
Cotinine test 
Alcohol breathurine test 
Switched the 
Alcohol 
Breath Test to 
the Alcohol 
Urine Test due 
to COVID-19 
pandemic at 
screening and 
Check-in 
visits. 
Updated other 
drug screening 
substances per 
site 
requirement.  
24  
58 
a Only analyzed at Screening. 
b After screening, on-study lipids will include 
triglycerides, VLDL-C, LDL-C, HDL-C, total 
cholesterol, Apo A1, and total Apo B. 
c Part 1 and Part 2 screening, and on study serum 
Lp(a) samples will be analyzed by a central 
laboratory of Covance Shanghai. 
a Only analyzed at Screening. 
b After screening, on-study lipids will include 
triglycerides, VLDL-C, LDL-C, HDL-C, total 
cholesterol, Apo A1, and total Apo B. 
Changed from 
Covance  
Shanghai to a 
Sponsor 
designated lab 
Page 103 of 266


Page 19 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
 
c Part 1 and Part 2 screening, and on study serum 
Lp(a) samples will be analyzed by a 
centralSponsor-designated laboratory of 
Covance Shanghai. 
 
25  
59 
Test 
Volume 
per blood 
sample 
(mL) 
Maximu
m 
number 
of blood 
samples 
Total 
amount 
of blood 
(mL) 
Clinical 
Chemistry 
and 
Hematolo
gy 
12 
12 
144 
Coagulati
on 
3 
9 
27 
Serum 
Pregnanc
ya 
5 
1 
5 
FSHb 
5 
1 
5 
Serology 
9 
1 
9 
PK 
4 
17 
68 
PD  
6 
21 
126 
Anti-
AMG 890 
Antibody 
4 
3 
12 
Total: 
396 
 
Test 
Volum
e per 
blood 
sample 
(mL) 
Maximu
m 
number 
of blood 
samples 
Total 
amount 
of blood 
(mL) 
Clinical 
Chemist
ry and 
Hematol
ogy 
12 
12 
144 
Coagula
tion 
3 
9 
27 
Serum 
Pregnan
cya 
5 
1 
5 
FSHb 
5 
1 
5 
Serolog
y 
9 
1 
9 
PK 
4 
17 
68 
PD 
Lp(a) 
65 
2114 
12670 
PD: 
Lipid 
panel 
8.5 
7 
59.5 
Updated total 
blood volumes 
to be 
collected.  
Page 104 of 266


Page 20 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
Anti-
AMG 
890Olp
asiran 
Antibod
y 
4 
3 
12 
Total: 
396399.
5 
26  
68 
A subject who is rescreened is not required to 
sign another ICF if the rescreening occurs within 
28 days from the previous ICF signature date. 
A subject who is rescreened is not required to 
sign another ICF if the rescreening occurs within 
2840 days from the previous ICF signature date. 
Updated the 
screening 
period to 40 
days.  
27  
69 
 
Records and documents, including signed 
ICFs, pertaining to the conduct of this 
study must be retained by the Investigator 
in the study site archive for 25 years after 
the end of the study unless local 
regulations or institutional policies 
require a longer retention period. No 
records may be destroyed during the 
retention period without the written 
approval of the Sponsor. No records may 
be transferred to another location or party 
without written notification to the 
Sponsor. 
 
Records and documents, including signed 
ICFs, pertaining to the conduct of this 
study must be retained by the Investigator 
in the study site archive for 2515 years 
after the end of the study unless local 
regulations or institutional policies 
require a longer retention period. No 
records may be destroyed during the 
retention period without the written 
approval of the Sponsor. No records may 
be transferred to another location or party 
without written notification to the 
Sponsor. 
Updated the 
archival 
period of 
documentation 
from 25 years 
to 15 years per 
the site 
requirement. 
Page 105 of 266


Page 21 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
 
28  
76 
-28 to -2 
-28-40 to -2 
Updated 
screening 
period to 40 
days.  
29  
76 
Alcohol Breath Test 
Alcohol BreathUrine Test 
Updated the 
alcohol test in 
Table 5 
Schedule of 
assessment.  
30  
76 
Anti-AMG 890 Antibody tested at Day -1 
Anti-AMG 890Olpasiran Antibody tested at Day 
1 predose 
Updated 
collection 
timepoint 
ensure subject 
ID designation 
on sample 
collection 
tube. 
31  
77 
 e Sitting blood pressure, sitting heart rate, 
respiratory rate and temperature. Heart rate and 
BP will be measured using the same arm for 
each reading after the subject has been resting 
in the sitting position for at least 5 minutes. 
…… 
m Part 1 and Part 2 screening, and on study serum 
Lp(a) samples will be analyzed by a central 
laboratory of Covance Shanghai.  
 
e Sitting blood pressure, sitting heartpulse rate, 
respiratory rate and temperature. HeartPulse 
rate and BP will be measured using the same 
arm for each reading after the subject has been 
resting in the sitting position for at least 
5 minutes. 
…… 
m Part 1 and Part 2 screening, and on study serum 
Lp(a) samples will be analyzed by a 
centralSponsor-designated laboratory of 
Covance Shanghai. 
Updated to 
pulse rate per 
site 
requirement.  
Changed from 
Covance  
Shanghai to a 
Sponsor 
designated 
lab. 
Page 106 of 266


Page 22 of 22 
 
No. 
Page, 
Original 
Amendment 
Rationale 
32  
79 
d Sitting blood pressure, sitting heart rate, 
respiratory rate and temperature. Heart rate and 
BP will be measured using the same arm for 
each reading after the subject has been resting 
in the sitting position for at least 5 minutes. 
…… 
j Part 1 and Part 2 screening, and on study serum 
Lp(a) samples will be analyzed by a central 
laboratory of Covance Shanghai. 
d Sitting blood pressure, sitting heartpulse rate, 
respiratory rate and temperature. HeartPulse 
rate and BP will be measured using the same 
arm for each reading after the subject has been 
resting in the sitting position for at least 
5 minutes. 
…… 
j Part 1 and Part 2 screening, and on study serum 
Lp(a) samples will be analyzed by a 
centralSponsor-designated laboratory of 
Covance Shanghai. 
Updated to 
pulse rate per 
site 
requirement.  
Changed from 
Covance  
Shanghai to a 
Sponsor 
designated 
lab. 
 
Page 107 of 266

SAP_001.pdf: 
FTITLE PAGE 
Statistical Analysis Plan 
An Open-label, Single-dose Study to Evaluate the Pharmacokinetics, 
Pharmacodynamics, Safety and Tolerability of AMG 890 in Chinese 
Subjects with Elevated Serum Lipoprotein(a) 
SAP Version: 2 
SAP Status: Final 
SAP Date: 06 November 2022 
Investigational Product: AMG 890 
Protocol Reference: 20190095 
Covance Study: 8424665 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, California 91320 
USA 
Study Sites: 
The University of Hong Kong, Queen Mary 
Hospital, 102 Pokfulam Road, Hong Kong; 
Principal Investigator: 
,MBBCH, MD 
(Wales), FHKCP, FHKAM (Med), FRCP 
(Edin), FRCP (Lond) 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
Page 2 of 20
NCT Number: NCT04987320
This NCT number has been applied to the document
for purposes of posting on Clinicaltrials.gov


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 2 of 18 
Reference: ST-AD-031 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 5 
2. STUDY OBJECTIVES .......................................................................................................... 5 
2.1.  Primary Objective .......................................................................................................... 5 
2.2 Secondary Objective ........................................................................................................ 5 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 6 
4. STUDY DESIGN................................................................................................................... 6 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 7 
6. STUDY TREATMENTS ....................................................................................................... 8 
7. DEFINITIONS OF ANALYSIS SETS ................................................................................. 8 
7.1. All Subjects Analysis Set ................................................................................................ 8 
7.2. Safety Analysis Set ......................................................................................................... 8 
7.3. Pharmacokinetic Analysis Set ......................................................................................... 8 
7.4. Pharmacodynamic Analysis Set ...................................................................................... 8 
8. STATISTICAL METHODOLOGY ...................................................................................... 9 
8.1. General ............................................................................................................................ 9 
8.1.1. Calculation of the Summary Statistics ..................................................................... 9 
8.1.2. Repeat and Unscheduled Readings ........................................................................ 10 
8.2. Subject Disposition and Analysis Set Assignment ....................................................... 10 
8.3. Screening Demographics .............................................................................................. 10 
8.4. Prior and Concomitant Medication ............................................................................... 10 
8.5. Pharmacokinetic and Pharmacodynamic Assessments ................................................. 10 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 10 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 13 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 13 
8.5.4. Pharmacodynamic Statistical Methodology ........................................................... 13 
8.6. Safety and Tolerability Assessments ............................................................................ 14 
8.6.1. Adverse Events ....................................................................................................... 14 
Page 3 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 3 of 18 
 
 
Reference: ST-AD-031 
8.6.2. Clinical Laboratory Parameters .............................................................................. 15 
8.6.3. Vital Signs Parameters ........................................................................................... 16 
8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 16 
8.6.5. Other Assessments ................................................................................................. 16 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 16 
9. INTERIM ANALYSES ....................................................................................................... 16 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 16 
11. REFERENCES .................................................................................................................. 16 
12. APPENDICES ................................................................................................................... 17 
Page 4 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 4 of 18 
 
 
Reference: ST-AD-031 
LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
ADaM 
analysis data model 
AE 
adverse event 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from time zero to infinity 
AUClast 
area under the concentration-time curve from time zero to time of last 
quantifiable concentration (tlast) 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
Cmax 
maximum serum concentration 
CL/F 
apparent total body clearance 
CSR 
clinical study report 
ECG 
electrocardiogram 
EOS 
end of study 
ICF 
informed consent form 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
λz 
elimination rate constant 
Lp(a) 
Lipoprotein(a) 
MedDRA 
Medical Dictionary for Regulatory Activities 
NC 
not calculated 
PD 
pharmacodynamic 
PK 
pharmacokinetic(s) 
R2 
correlation coefficient of terminal elimination phase 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tmax 
time of maximum serum concentration 
Vz/F 
apparent volume of distribution during the terminal elimination phase 
WHODrug 
World Health Organization Drug Dictionary  
%AUCextrap 
percentage of AUC that is due to extrapolation from the last measurable 
concentration to infinity 
Page 5 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 5 of 18 
 
 
Reference: ST-AD-031 
1. INTRODUCTION 
This SAP has been developed in alignment with the clinical study protocol (dated 07 Oct 
2020). 
This SAP describes the planned analysis of the pharmacokinetic (PK), pharmacodynamic 
(PD) and safety and tolerability data from this study. A detailed description of the planned 
TFLs to be presented in the clinical study report (CSR) is provided in the accompanying TFL 
shells document. 
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Amgen Inc. A limited amount of information about this study 
(eg, objectives, study design) is given to help the reader’s interpretation. This SAP must be 
finalized prior to the lock of the clinical database for this study. When the SAP and TFL 
shells are approved, they will serve as the template for this study’s CSR. 
Significant changes from the protocol-specified analyses are described in section 10 of this 
SAP. If post-hoc analyses are required to supplement the planned analyses described in this 
SAP, they may be performed and will be identified accordingly in the CSR. Any substantial 
deviations from this SAP will be agreed with Amgen Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2 
The document history is presented in Appendix 1. 
2. STUDY OBJECTIVES 
2.1.  Primary Objective 
The primary objective of the study is: 
 to evaluate the PK of a single dose of AMG 890 in Chinese subjects with elevated 
serum lipoprotein(a) (Lp(a)). 
2.2 Secondary Objective 
The secondary objectives of the study are: 
 to evaluate the safety and tolerability of a single dose of AMG 890 in Chinese 
subjects with elevated serum Lp(a). 
 to evaluate the pharmacodynamic of a single dose of AMG 890 in Chinese subjects 
with elevated serum Lp(a). 
Page 6 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 6 of 18 
Reference: ST-AD-031 
3. STUDY ENDPOINTS
3.1. Primary Endpoints 
The primary endpoints are: 

maximum serum concentration (Cmax);

area under the serum concentration-time curve (AUC);

Additional PK parameters may include, but are not limited to: time to maximum
observed concentration (tmax), half-life (t1/2), apparent volume of distribution during
the terminal elimination phase (Vz/F), and apparent total body clearance (CL/F).
3.2. Secondary Endpoints 
The secondary endpoints are: 

Treatment-emergent adverse events;

clinical laboratory tests;

12-lead electrocardiograms (ECGs);

vital signs;

lipids;

serum Lp(a).
4. STUDY DESIGN
This study is an open-label, randomized, single-dose, parallel-group study in Chinese subjects 
with elevated serum Lp(a) to assess the PK, safety and tolerability, and PD of AMG 890. 
Subjects will be randomized in a 1:1 ratio to receive a single SC dose of AMG 890 at 
 mg 
(Group A) or 
 mg (Group B). A total of approximately 24 subjects (12 per group) will be 
enrolled in this study.  
Subjects must be living in mainland China, Hong Kong, or Taiwan, and be of Chinese 
ancestry with an age of 18 to 60 years old, and have body mass index (BMI) of 18 to 32 kg/ 
m2 and serum Lp(a) ≥ 70 nmol/L (or approximately ≥ 27 mg/dL). 
Subjects will be assigned to 1 of 2 treatment groups shown in Table 1. 
Table 1:  
Treatment Groups 
Group 
Number of subjects 
Dose 
Page 7 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 7 of 18 
 
 
Reference: ST-AD-031 
A 
12 
 mg SC 
B 
12 
 mg SC 
 An overview of the study design is shown in Figure 1 below. 
 
Figure 1: Study Schematic 
 
 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration. Subjects will be admitted into the clinic on Day -1 and 
be confined to the clinic until discharge on Day 4. Subjects will return to the clinic for 
outpatient visits on Days 7, 15, 29, 57, 85, 113, 155, and 183, and at the End of Study (EOS) 
visit on Day 225. A telephone visit will be scheduled for TEAE assessments on Day 211. The 
total duration of study participation for each subject (from Screening through EOS visit) is 
anticipated to be approximately 253 days (36 weeks). 
The start of the study is defined as the date the first subject signs an Informed Consent Form 
(ICF). The point of enrollment occurs at the time of subject randomization number allocation. 
The enrollment date is the same as the randomization date. The EOS for overall study is 
defined as the date of the last subject’s last assessment (scheduled or unscheduled).  
5. SAMPLE SIZE JUSTIFICATION 
Approximately 24 subjects (12 per group) will be enrolled in the study. No formal statistical 
hypothesis testing will be performed. The sample size of 12 subjects per group is based on 
studies of similar nature and was not based on power calculations. Considering a 33.3% drop-
out rate, 8 subjects per cohort provides an approximately 90% confidence of observing a case 
of a TEAE in each cohort at an incidence of 25%. 
Page 8 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 8 of 18 
 
 
Reference: ST-AD-031 
6. STUDY TREATMENTS 
The study treatment names and ordering to be used in the TFLs are presented in Table 2 
below. 
 
 
 
 
Table 2: 
Presentation of Study Treatments in TFLs 
Study Treatment 
Treatment 
Abbreviation 
Order in 
TFLs 
Group A: 
 mg administered as a single 1 mL 
(
 mg/mL) SC injection 
 mg AMG 890 
1 
Group B: 
 mg administered as three 1.0 mL 
(
 mg/mL) SC injections 
 mg AMG 890  
2 
 
All treatments described above are the planned treatments. Subject disposition and baseline 
will be summarized by randomized treatment group, PK and safety analysis will be 
summarized by actual treatment received., and dose levels will be displayed in increasing 
order. 
7. DEFINITIONS OF ANALYSIS SETS 
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to analysis sets. 
7.1. All Subjects Analysis Set 
The all subjects analysis set will include all randomized subjects. 
7.2. Safety Analysis Set 
The safety analysis set will include all randomized subjects who received AMG 890.  
7.3. Pharmacokinetic Analysis Set 
The PK analysis set will include all randomized subjects who received AMG 890 and have 
evaluable PK data. 
7.4. Pharmacodynamic Analysis Set 
The PD analysis set will include all randomized subjects who received AMG 890 and have 
evaluable PD data. 
Page 9 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 9 of 18 
 
 
Reference: ST-AD-031 
8. STATISTICAL METHODOLOGY 
8.1. General 
Listings will be provided for all data captured in the database, with the exception of medical 
history. Listings will include all subjects in the all subjects analysis set and include data up to 
the point of study completion or discontinuation. Any subject who discontinued the study will 
be listed in the applicable listing. Summaries and statistical analyses will include the subjects 
assigned to the relevant analysis sets based on data type.  
Data analysis will be performed using the SAS® statistical software package Version 9.4 or 
higher. 
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.1. Pinnacle 21 Community 
Validator Version 4.2.1 will be utilized to ensure compliance with CDISC standards.  
Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses and any parameter derivations. 
8.1.1. Calculation of the Summary Statistics 
For continuous data the following rules will be applied: 
● Missing values will not be imputed, unless specifically stated otherwise. 
● Unrounded data will be used in the calculation of summary statistics. 
● If number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum. 
● As Early Termination data is not associated with any scheduled timepoint, it will be 
excluded from all calculations of summary statistics. 
For categorical data the following rules will be applied: 
● If the categories of a parameter are ordered (eg, adverse event [AE] severity), all 
categories between the possible minimum and maximum categories will be included, 
even if n = 0 for a given category. If the categories are not ordered (eg, race), only those 
categories for which there is at least 1 subject represented will be included. 
● Missing values will not be imputed, or unless specifically stated otherwise. A ‘missing’ 
category will be included for any parameter for which information is missing. This will 
ensure that the population size totals are consistent across different parameters. 
Page 10 of 20


SAP 
CONFIDENTIAL 
Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 10 of 18 
 
 
Reference: ST-AD-031 
8.1.2. Repeat and Unscheduled Readings 
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 
be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value. 
The original value will be replaced by the last associated repeat value in all calculations. 
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations. 
8.2. Subject Disposition and Analysis Set Assignment 
Subject disposition and analysis set assignment will be listed. 
A summary table will be provided, based on the all subjects analysis set. 
8.3. Screening Demographics  
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed. 
A summary table will be provided, based on the safety analysis set. 
8.4. Prior and Concomitant Medication 
Prior medication will be defined as medication that ends prior to the first dose. Concomitant 
medication will be defined as medication that starts after dosing or starts but does not end 
prior to dosing. 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version Month 2020 (or later if upversioned 
during the study). Prior and concomitant medications will be listed.  
8.5. Pharmacokinetic and Pharmacodynamic Assessments 
8.5.1. Pharmacokinetic Analysis 
The following PK parameters will be determined where possible from the serum 
concentrations of AMG 890 using non compartmental methods in validated software 
program, Phoenix WinNonlin (Certara, Version 8.1 or higher): 
The following parameters for OM will be summarized and listed: 
Parameter 
Unitsa 
Definition 
AUClastb 
h*ng/mL 
area under the serum concentration-time curve from time 0 to the 
time of last quantifiable concentration (tlast) 
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Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
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Reference: ST-AD-031 
AUCinfb 
h*ng/mL 
area under the serum concentration-time curve from time 0 
extrapolated to infinity 
Cmax 
ng/mL 
maximum observed concentration 
tmax 
h 
time to maximum observed concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total body clearance 
Vz/F 
L 
apparent volume of distribution during the terminal elimination 
phase  
%AUCextrap 
% 
percentage of AUC due to extrapolation from the last quantifiable 
concentration to infinity 
a Units are based on concentration units (provided by bioanalytical lab) and dose units used in the study. 
b AUCs will be calculated using the linear trapezoidal linear interpolation rule. 
 
Additional pharmacokinetic parameters may be determined where appropriate. 
Pharmacokinetic analysis will, where possible, be carried out using actual blood sampling 
times post dose. If actual times are missing, nominal times may be used with sponsor 
approval.  
Cmax, and tmax will be obtained directly from the concentration-time profiles. If Cmax occurs at 
more than 1 timepoint, tmax will be assigned to the first occurrence of Cmax.  
8.5.1.1. Criteria for the Calculation of an Apparent Terminal Elimination Rate 
Constant and Half-Life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and generally will be the first point at which there is no systematic deviation from 
the log-linear decline in concentrations.  
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
coefficient for determination of exponential fit (R2) of the regression line is ≥0.8. Parameters 
requiring λz in their calculation (eg, AUCinf, %AUCextrap, t1/2, CL/F, and Vz/F) will only be 
calculated if the R2 value of the regression line is ≥ 0.8.  
The following regression-related diagnostic PK parameters will be determined:  
Parameter 
Units 
Definition 
λz 
1/h 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio 
NA 
time period over which λz was determined as a ratio of t1/2 
R2 
NA 
coefficient for determination of exponential fit 
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Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 12 of 18 
 
 
Reference: ST-AD-031 
Where possible, the span of time used in the determination of λz (ie the difference between λz 
Upper and λz Lower) should be ≥2 half-lives. If the λz Span Ratio is <2, the robustness of the 
t1/2 values will be discussed in the CSR. 
Per Sponsor request, the half-life calculation is based on the beta phase of the elimination 
instead of terminal phase elimination. This decision is based on the PK properties of 
AMG890 where the terminal elimination phase constitutes a very small fraction of the total 
exposure (AUC) and the concentrations at terminal phase are close to the LLOQ value.  
8.5.1.2. Criteria for Calculation and Reporting of Area Under the Concentration-time 
Curve 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should follow Cmax.  
AUCinf values where the percentage extrapolation is less than or equal to 20% will be 
reported. AUCinf values where the percentage extrapolation is greater than 20% will be listed 
but flagged and excluded from descriptive statistics. 
8.5.1.3. Criteria for Handling Below the Limit of Quantification or Missing 
Concentrations for Pharmacokinetic Analysis 
Serum concentration values that are below the limit of quantification (BLQ) will be set to a 
value of zero, with the following defined exceptions which will be set to missing: 
● Any embedded BLQ value (between 2 quantifiable concentrations). 
● BLQ values following the last quantifiable concentration in a profile. 
● If an entire concentration-time profile is BLQ, it will be excluded from PK analysis. 
Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile will 
be deemed to have terminated and any further quantifiable concentrations will be set to 
missing for the calculation of the PK parameters unless they are considered to be a true 
characteristic of the profile of the drug. 
If a predose serum concentration is missing, it may be set to zero by default. 
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in CSR.   
Quantifiable predose concentration values in the first treatment period (if applicable) will be 
considered anomalous and set to missing for the PK analysis.  
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Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
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Reference: ST-AD-031 
If the predose concentration is >5% of Cmax in the second treatment period (if applicable), all 
PK concentration and parameter data may be excluded from the summary statistics and 
statistical analysis for that period at the discretion of the Pharmacokineticist. 
8.5.2. Presentation of Pharmacokinetic Data 
If the actual time of sample collection deviates from the nominal time by more than ± 20%, 
the concentration may be flagged and excluded from summary statistics. Individual 
concentrations that are deemed to be anomalous will be flagged in the listings and excluded 
from the summary statistics.   
For PK concentration data the following rules will be applied: 
● Values that are BLQ will be set to 0 for calculation of summary statistics. 
● Arithmetic mean or median that are BLQ will be presented as 0. 
For PK parameters the following rule will be applied: 
● Geometric mean and coefficient of variation will not be calculated for tmax. 
8.5.3. Pharmacokinetic Statistical Methodology 
All PK concentrations and parameters will be listed. 
Summary tables, mean (+ standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment group and time post dose will be provided for serum PK 
concentrations. All figures will be produced on both linear and semi-logarithmic scales. The 
+SD bars will be only displayed on the linear scale. 
Summary tables by treatment group will be provided for all PK parameters, with the 
exception of regression-related PK parameters. Separate summary tables by treatment group 
and time interval will be provided for excretion parameters. 
8.5.4. Pharmacodynamic Statistical Methodology  
Venous blood samples (approximately 6 mL) will be collected for measurement of Lp(a) at 
scheduled times.  
Lipid panel will include triglycerides, very low-density lipoprotein cholesterol (VLDL-C), 
low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-
C), total cholesterol, apolipoprotein A1 (ApoA1) and total apolipoprotein B (Apo B). At 
screening, lipid panel will measure triglycerides only. Venous blood samples (approximately 
6 mL) will be collected for measurement of lipid panel at scheduled times. The lipid panel 
will be analyzed by a central lab of Covance Shanghai. 
All PD parameters will be listed.  
Summary tables and mean change and percent change from baseline (+ SE) figures by 
treatment and timepoint will be provided for all PD parameters based on PD analysis set. 
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Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 14 of 18 
 
 
Reference: ST-AD-031 
Baseline is defined as the mean of last two non-missing values predose. If only 1 predose 
value is available then that value will be used as the baseline. 
Values below the limit of quantification will be set to BLQ for the calculation of summary 
statistics.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to BLQ , whereas >x and ≥x values will be set to x.  
No inferential statistical analyses are planned.  
8.6. Safety and Tolerability Assessments 
8.6.1. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 24.0 (or higher if upversioned during the study). 
A treatment-emergent adverse event (TEAE) will be defined as any AE that starts on or after 
the first dose of investigational product (as determined by the flag indicating if the adverse 
event started prior to the first dose or not on the AE electric case report form) and up to EOS.  
A treatment related TEAE will be defined as a TEAE with a relationship of possibly related 
or related to the study treatment, as determined by the investigator. 
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of  
dosing for TEAEs only. 
The subject incidence of TEAE and the number of TEAEs will be summarized for the 
following categories based on safety analysis set: 
● TEAEs (overall, serious, leading to study discontinuation, and leading to death) by 
treatment group 
● TEAEs by severity and treatment group 
● Treatment-related TEAEs (overall, serious, leading to study discontinuation, and 
leading to death) by treatment group 
● Treatment-related TEAEs by severity and treatment group 
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs events by the following: 
● System organ class, preferred term, and treatment group 
● Preferred term and treatment group 
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Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 15 of 18 
 
 
Reference: ST-AD-031 
For the AE data the following rules will apply: 
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to the first dose. 
● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, the treatment relationship will be kept as missing. 
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, the 
minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of the last dose is 01MAY2019/08:00 and recorded start 
date/time of an adverse event is 03MAY2019, then the minimum possible onset time 
will be calculated by assuming the an adverse event started at the first hour and minute 
of 03MAY2019 [03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 
in the listing). 
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an adverse event date/time is 01MAY2019/08:00 and its 
recorded end date/time is 03MAY2019, then the maximum possible duration will be 
calculated by assuming the adverse event ended at the last hour and minute of 
03MAY2019 [03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the 
listing). 
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted as missing severity. 
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment group, this will be counted as separate 
TEAEs for that treatment under each specific severity recorded. 
8.6.2. Clinical Laboratory Parameters 
All clinical laboratory parameters will be listed; any value outside the clinical reference range 
will be flagged. Separate listings will be provided for any parameter for which there is any 
individual subject value outside the respective clinical reference range.  
Summary tables by timepoint along with change from baseline and percent change from 
baseline will be provided for clinical chemistry and hematology parameters based on safety 
analysis set. The baseline is defined as the last reading before dosing. 
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags and calculation of summary statistics, <x and ≤x values will be set 
to BLQ, whereas >x and ≥x values will be set to x. 
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Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 16 of 18 
 
 
Reference: ST-AD-031 
8.6.3. Vital Signs Parameters 
All vital signs parameters will be listed; any value outside the clinical reference range will be 
flagged.  
Summary tables along with change from baseline and percent change from baseline will be 
provided for all vital signs parameters based on safety analysis set. The baseline is defined as 
the last reading before dosing. 
8.6.4. 12-lead Electrocardiogram Parameters 
All 12-lead ECG parameters will be listed; any value outside the clinical reference range will 
be flagged.  
Summary tables by timepoint along with change from baseline and percent change from 
baseline will be provided for all 12-lead ECG parameters based on safety analysis set. The 
baseline is defined as the last reading before dosing. 
8.6.5. Other Assessments 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only. 
Medical history will not be listed.  
8.6.6. Safety and Tolerability Statistical Methodology 
No inferential statistical analyses are planned. 
9. INTERIM ANALYSES 
No interim analyses are planned for this study. 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES 
There were no significant changes from the protocol-specified analyses. 
11. REFERENCES 
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998. 
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
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Covance Study: 8424665 
Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 17 of 18 
 
 
Reference: ST-AD-031 
12. APPENDICES 
Appendix 1: 
Document History 
Document 
Version, 
Status, Date 
Change 
Made 
By 
Date of 
Change 
Change 
after DB 
lock? 
Client 
Approval? Summary/Reason for Changes 
Version 1, Final, 11 
November 2020 
 
 
 
 
Not applicable; the first version 
Version 1, Final, 
Working Version 
WX 
12Jan2020 
NA 
NA 
Corrected Typo in the SAP. Change wording from: 
The following parameters for OM will be summarized and listed: 
To: 
The following parameters for AMG 890 will be summarized and listed: 
 
Version 1, Final, 
Working Version 
WX 
24Jun2021 
NA 
NA 
Updated the following per Protocol V2.0 Dated 03May2021: 
1) 
Update Globally, Change all AMG 890 in SAP and TFL shells to “Olpasiran” 
2) 
SAP p7: update screening period from “28” to “40” days in both language and figure 1. 
3) 
SAP p8: update
mg dosage from “three 1.0 mL” to “two 1.5 mL” 
4) 
SAP p7: update duration of study from “253 days (36 weeks).” to “265 days (about 38 weeks)” 
correspondingly in both language and figure 1; 
Version 1, Final, 
Working Version 
WX 
27Oct2021 
NA 
NA 
Typo correction, updated MedDRA version to be 24.0 instead of “XX.X” to match the DMP on p14 of the SAP 
narrative. 
Version 1, Final, 
Working Version 
WX 
10Jan2022 
NA 
NA 
Corrected Pinnacle 21 version: 
Change from: Pinnacle 21 Community Validator 4.2.1 
To: Pinnacle21 Community Validator 3.1.2 
Version 1, Final, 
Working Version 
WX 
02Feb2022 
NA 
NA 
Corrected Figure title per sponsor comment: 
Update the Figure titles from: 
Figure 14.2.2-1 Arithmetic Mean (+SD) Lp(a) Concentration-time Profiles 
Figure 14.2.2-2 Arithmetic Mean (+SD) Lp(a) Change from Baseline Concentration-time Profiles 
Figure 14.2.2-3 Arithmetic Mean (+SD) Lp(a) Percent Change from Baseline Concentration-time Profiles 
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Protocol Reference: 20190095 
Version 2, Final, 06 December2022 
Page 18 of 18 
 
 
Reference: ST-AD-031 
To: 
Figure 14.2.2-1 Arithmetic Mean (+SD) Pharmacodynamic Parameters Concentration-time Profiles 
Figure 14.2.2-2 Arithmetic Mean (+SD) Pharmacodynamic Parameters Change from Baseline Concentration-time 
Profiles 
Figure 14.2.2-3 Arithmetic Mean (+SD) Pharmacodynamic Parameters Percent Change from Baseline Concentration-
time Profiles 
Version 1, Final, 
Working Version 
WX 
24Aug2022 
NA 
NA 
Section 8.5.1.1 
Updated PK language typo from: 
Parameters requiring λz in their calculation (eg, AUCinf, %AUCextrap, t1/2, CL/F, and Vz/F) will only be calculated 
if the R2 value of the regression line is ≥ 0.7. 
To: 
Parameters requiring λz in their calculation (eg, AUCinf, %AUCextrap, t1/2, CL/F, and Vz/F) will only be calculated 
if the R2 value of the regression line is ≥ 0.8. 
Version 2, Final 
WX 
06Dec2022 
NA 
Y 
Amended the front page study site name, address and PI’s name and credential. 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan (SAP) Approval Form 
 
COVANCE INC. CONFIDENTIAL 
Page 1 of 1 
ST-AD-030 version 01 
Type of Approval (select one) :   
 SAP 
 
Sponsor Name: 
Amgen Inc. 
Sponsor 
Protocol/CIP ID: 
20190095 
Covance 
Study ID: 
8424665 
SAP text filename: 
Amgen_890_20190095_SAP 
_06Dec2022_Final 
TFL shells 
filename: 
Amgen_890_20190095_TFL 
_06Dec2022_Final 
Version: 
2.0 
Date: 
06Dec2022 
 
 
Covance Approval(s): 
Lead Statistician 
Approval Signature 
Biostatistician 
Date 
 
 
 
 
Sponsor Approval(s): 
By signing below when the statistical analysis plan (SAP) is considered final, the 
signatories agree to the analyses to be performed for this study and to the format of 
the associated tables, figures, and listings (TFLs). Once the SAP has been signed, 
programming of the Analysis Dataset Model (ADaM) datasets and TFLs based on these 
documents can proceed. Any modifications to the SAP text and TFL shells made after 
signing may result in a work-scope change. 
 
Approval Signature 
Print Name 
Job Title 
Date 
 
 
 
N/A 
 
Please scan/email completed form(s) to the Lead Statistician listed below: 
Printed Name/Title: 
 Biostatistician 
Email: 
 
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