Conditions: Cardiovascular Disease
Keywords: Olpasiran AMG 890 siRNA lipoprotein (a) Lp(a) Cardiovascular Cardiovascular disease Atherosclerotic cardiovascular disease Cholesterol Apolipoprotein (B) Hyperlipidemia Dyslipidemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 281
Healthy volunteers: no

Brief summary:
Evaluate the effect of olpasiran administered subcutaneously (SC) compared with placebo, on percent change from baseline in lipoprotein(a) (Lp\[a\]).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: Olpasiran intervention 2: Placebo
Intervention descriptions: intervention 1: Dose 1 Dose 2 Dose 3 Dose 4 intervention 2: Dose 5

Protocol document:
Prot_000.pdf: 
Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 1 of 99 
CONFIDENTIAL  
 
 
Title Page 
Protocol Title: 
A Double-blind, Randomized, Placebo-controlled 
Phase 2 Study to Evaluate Efficacy, Safety, and 
Tolerability of Olpasiran (AMG 890) 
(a GalNAc-conjugated Small Interfering RNA 
[siRNA]) in Subjects With Elevated Lipoprotein(a) 
Short Protocol Title: 
Olpasiran trials of Cardiovascular Events And 
LipoproteiN(a) reduction – DOSE Finding Study 
(OCEAN[a]-DOSE) 
Protocol Number: 
20180109 
Investigational Product: 
Olpasiran (AMG 890)  
Sponsor 
Name of Sponsor: 
Amgen Inc. 
Address: 
One Amgen Center Drive, Thousand Oaks, CA 
91320, USA 
Telephone Number: 
1 (805) 447-1000 
Protocol 
Approver 
Name: 
 
Function: 
VP Global Development 
 
Key 
Sponsor 
Contact 
Name: 
 
Address: 
One Amgen Center Drive, Thousand Oaks, CA 
91320, USA 
Telephone Number: 
 
Email Address: 
 
 
EudraCT Number: 
2019-003688-23 
NCT Number: 
NCT04270760 
Protocol Version Date: 
Document Version 
Date 
Original 
09 November 2019 
Amendment 1 
25 November 2020 
Amendment 2 
01 April 2021 
Amendment 3 
02 May 2022 
Data Elements Standards 
Version: 
6 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  The format and content of this protocol is aligned 
with Good Clinical Practice:  Consolidated Guidance (ICH E6). 
 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 2 of 99 
CONFIDENTIAL  
 
 
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; for all other countries, Amgen’s general number in the US, 
1-805-447-1000. 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 3 of 99 
CONFIDENTIAL  
 
 
Investigator’s Agreement: 
I have read the attached protocol entitled A Double-blind, Randomized, 
Placebo-controlled Phase 2 study to evaluate Efficacy, Safety, and Tolerability of 
Olpasiran (AMG 890) (a GalNAc-conjugated Small Interfering RNA [siRNA]) in subjects 
with elevated lipoprotein(a), dated 02 May 2022, and agree to abide by all provisions set 
forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 4 of 99 
CONFIDENTIAL  
 
 
Table of Contents 
1. 
Protocol Summary .................................................................................................. 8 
1.1 
Synopsis ..................................................................................................... 8 
1.2 
Study Schema ........................................................................................... 12 
1.3 
Schedule of Activities (SoA) ...................................................................... 13 
2. 
Introduction ........................................................................................................... 18 
2.1 
Study Rationale ......................................................................................... 18 
2.2 
Background ............................................................................................... 19 
2.2.1 
Disease ..................................................................................... 19 
2.2.2 
Amgen Investigational Product Background:  
Olpasiran ................................................................................... 21 
2.3 
Benefit/Risk Assessment ........................................................................... 22 
3. 
Objectives and Endpoints ..................................................................................... 24 
4. 
Study Design ........................................................................................................ 26 
4.1 
Overall Design .......................................................................................... 26 
4.2 
Number of Subjects ................................................................................... 27 
4.2.1 
Replacement of Subjects ........................................................... 27 
4.2.2 
Number of Sites ......................................................................... 27 
4.3 
Justification for Investigational Product Dose ............................................ 27 
4.4 
End of Study ............................................................................................. 28 
4.4.1 
End of Study Definition .............................................................. 28 
4.4.2 
Study Duration for Subjects ....................................................... 29 
4.5 
Patient Input on Study Design ................................................................... 29 
5. 
Study Population .................................................................................................. 29 
5.1 
Inclusion Criteria ....................................................................................... 29 
5.2 
Exclusion Criteria ...................................................................................... 30 
5.3 
Lifestyle Considerations ............................................................................ 32 
5.3.1 
Activity ....................................................................................... 32 
5.4 
Subject Enrollment .................................................................................... 32 
5.5 
Screen Failures ......................................................................................... 32 
5.6 
Washout Period/Run-in Period/Invasive Procedure(s) ............................... 33 
6. 
Treatments ........................................................................................................... 33 
6.1 
Treatment(s) Administered ........................................................................ 33 
6.1.1 
Investigational Products ............................................................ 33 
6.1.2 
Medical Devices ........................................................................ 35 
6.1.3 
Other Protocol-required Therapies ............................................ 35 
6.1.4 
Other Treatment Procedures ..................................................... 35 
6.1.5 
Product Complaints ................................................................... 35 
6.1.6 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 35 


Product:  Olpasiran 
Protocol Number:  20180109 
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CONFIDENTIAL  
 
 
6.2 
Dose Modification ...................................................................................... 36 
6.2.1 
Dose-cohort Study Escalation/De-escalation and 
Stopping Rules .......................................................................... 36 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 36 
6.2.2.1 
Amgen Investigational Product:  Olpasiran .............. 36 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 36 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 36 
6.4 
Measures to Minimize Bias:  Randomization and Blinding ......................... 36 
6.4.1 
Method of Treatment Assignment .............................................. 36 
6.4.2 
Blinding ..................................................................................... 37 
6.4.2.1 
Site Personnel Access to Individual 
Treatment Assignments .......................................... 37 
6.4.2.2 
Access to Individual Subject Treatment 
Assignments by Amgen or Designees ..................... 37 
6.5 
Treatment Compliance .............................................................................. 38 
6.6 
Treatment of Overdose ............................................................................. 38 
6.7 
Prior and Concomitant Treatment ............................................................. 38 
6.7.1 
Prior Treatment ......................................................................... 38 
6.7.2 
Concomitant Treatment ............................................................. 38 
7. 
Discontinuation Criteria ......................................................................................... 39 
7.1 
Discontinuation of Study Treatment........................................................... 39 
7.2 
Discontinuation From the Study ................................................................ 40 
7.2.1 
Reasons for Removal From Washout Period, Run-in 
Period, or Invasive Procedures ................................................. 40 
7.2.2 
Reasons for Removal From Study ............................................. 40 
7.3 
Lost to Follow-up ....................................................................................... 41 
8. 
Study Assessments and Procedures .................................................................... 41 
8.1 
General Study Periods .............................................................................. 41 
8.1.1 
Screening, Enrollment, and/or Randomization ........................... 41 
8.1.2 
Treatment Period ....................................................................... 42 
8.1.3 
Extended Safety Follow-up ........................................................ 43 
8.1.4 
End of Study .............................................................................. 43 
8.2 
Description of General Study Assessments and Procedures ..................... 43 
8.2.1 
General Assessments ............................................................... 43 
8.2.1.1 
Informed Consent .................................................... 43 
8.2.1.2 
Demographics ......................................................... 43 
8.2.1.3 
Medical History ........................................................ 44 
8.2.1.4 
Physical Examination .............................................. 44 
8.2.1.5 
Physical Measurements .......................................... 45 
8.2.2 
Efficacy Assessments ................................................................ 45 
8.2.3 
Safety Assessments .................................................................. 45 


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8.2.3.1 
Vital Signs ............................................................... 45 
8.2.3.2 
Survival Status ........................................................ 46 
8.2.3.3 
Electrocardiograms (ECGs) ..................................... 46 
8.2.4 
Adverse Events and Serious Adverse Events ............................ 46 
8.2.4.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 46 
8.2.4.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 47 
8.2.4.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 47 
8.2.4.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 48 
8.2.4.5 
Safety Monitoring Plan ............................................ 48 
8.2.4.6 
Pregnancy and Lactation ......................................... 48 
8.2.5 
Clinical Laboratory Assessments ............................................... 49 
8.2.6 
Pharmacokinetic Assessments .................................................. 50 
8.2.6.1 
Pharmacokinetic Sub-study ..................................... 51 
8.2.7 
Pharmacogenetic Assessments................................................. 51 
8.2.8 
Antibody Testing Procedures ..................................................... 51 
8.2.9 
Biomarkers ................................................................................ 52 
8.2.9.1 
Biomarker Assessment to Determine 
Eligibility .................................................................. 52 
8.2.9.2 
Biomarker Assessment During the Study ................ 52 
8.2.10 
Optional Sub-studies ................................................................. 53 
8.2.11 
Other Assessments ................................................................... 53 
8.2.11.1 
PROMIS Global Health ........................................... 53 
8.2.11.2 
Exit Survey .............................................................. 53 
9. 
Statistical Considerations ...................................................................................... 54 
9.1 
Statistical Hypotheses ............................................................................... 54 
9.2 
Sample Size Determination ....................................................................... 54 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 54 
9.3.1 
Analysis Sets ............................................................................. 54 
9.3.2 
Covariates ................................................................................. 54 
9.3.3 
Subgroups ................................................................................. 55 
9.3.4 
Handling of Missing and Incomplete Data .................................. 55 
9.4 
Statistical Analyses ................................................................................... 55 
9.4.1 
Planned Analyses ...................................................................... 55 
9.4.1.1 
Administrative Interim Analyses for 
Efficacy ................................................................... 55 
9.4.1.2 
Primary Analysis ..................................................... 56 
9.4.1.3 
End of Treatment Period Analysis ........................... 56 
9.4.1.4 
Final Analysis .......................................................... 56 
9.4.2 
Methods of Analyses ................................................................. 56 


Product:  Olpasiran 
Protocol Number:  20180109 
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CONFIDENTIAL  
 
 
9.4.2.1 
General Considerations ........................................... 56 
9.4.2.2 
Efficacy Analyses .................................................... 57 
9.4.2.3 
Safety Analyses ...................................................... 57 
10. 
References ........................................................................................................... 59 
11. 
Appendices ........................................................................................................... 63 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 64 
11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 67 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 69 
11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ...................................... 78 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 89 
11.6 
Appendix 6.  Sample Storage and Destruction .......................................... 94 
11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ................................................................................................. 96 
List of Tables 
Table 1-1.  Schedule of Activities (Screening Through Week 24) .................................. 13 
Table 1-2.  Schedule of Activities-PK Sub-study ............................................................ 17 
Table 6-1.  Study Treatments ........................................................................................ 34 
Table 11-1.  Analyte Listing ........................................................................................... 67 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity .............................................. 97 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 12 
Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form .................. 84 
Figure 11-2.  Pregnancy and Lactation Notification Forms ............................................. 92 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 8 of 99 
CONFIDENTIAL  
 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled Phase 2 Study to 
Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) (a GalNAc-
conjugated Small Interfering RNA [siRNA]) in Subjects with Elevated Lipoprotein(a)  
Short Protocol Title:  Olpasiran trials of Cardiovascular Events And LipoproteiN(a) 
reduction – DOSE Finding Study (OCEAN[a]-DOSE) 
Study Phase:  2 
Indication:  Cardiovascular disease 
Rationale 
Study 20180109 is a double-blind, randomized, multicenter dose finding study in 
subjects with atherosclerotic cardiovascular disease and elevated lipoprotein(a) (Lp[a]).  
The primary objective is to test olpasiran subcutaneous (SC) once every 12 weeks 
(Q12W) compared with placebo on percent change from baseline in Lp(a) after 
36 weeks of treatment.  Additionally, an exploratory dose of 225 mg once every 24 
weeks (Q24W) will be evaluated.  Olpasiran is being developed for the treatment of 
patients with atherosclerotic cardiovascular disease and elevated Lp(a) to reduce the 
risk of cardiovascular events.  Lp(a) reductions of  80 from baseline are anticipated 
with olpasiran and it is expected that this level of reduction in Lp(a) may result in 
clinically meaningful cardiovascular benefit in patients with atherosclerotic 
cardiovascular disease (Kamstrup et al, 2009, Burgess et al, 2018, Lamina et al, 2019, 
Madsen et al, 2020).  Lp(a) baseline is defined in Section 9.4.2.1. 
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of olpasiran 
administered subcutaneous (SC) once 
every 12 weeks (Q12W) compared with 
placebo, on percent change from baseline 
in lipoprotein(a) (Lp[a]) after 36 weeks of 
treatment 
 
Percent change in Lp(a) from baseline at 
week 36 
Primary Estimand 
The primary estimand consists of: 
 
The target population, which is adults with atherosclerotic cardiovascular disease and 
elevated Lp(a)  
 
The primary variable, which is percent change from baseline in Lp(a) at week 36 
 
The intercurrent events which are the discontinuation of investigational product and 
excluded medication(s) taken during study.  For the primary estimand, the treatment effect 
will be estimated in subjects who are randomized and received at least 1 dose of 
investigational product regardless of the occurrence of these intercurrent events 
 
The summary measure, which is the difference between olpasiran and placebo in the 
mean percent change from baseline in Lp(a) at week 36 
 
The treatments to be compared are each olpasiran group vs. placebo 
The primary estimand is the difference between each olpasiran group and placebo in the mean 
percent change from baseline in Lp(a) at week 36 in adults with atherosclerotic cardiovascular 
disease and with elevated Lp(a) who are randomized and received at least 1 dose of 
investigational product, regardless of discontinuation of investigational product and excluded 
medication(s) taken during the study. 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
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Objectives 
Endpoints 
Secondary 
 
To evaluate the effect of olpasiran 
administered SC Q12W compared with 
placebo, on percent change from baseline 
in: 
- 
Lp(a) after 48 weeks of treatment 
- 
Low-density lipoprotein cholesterol 
(LDL-C) after 36 and 48 weeks of 
treatment 
- 
Apolipoprotein(B) (ApoB) after 36 and 
48 weeks of treatment 
 
Percentage change from baseline in:   
- 
Lp(a) at week 48 
- 
LDL-C at week 36 and week 48 
- 
ApoB at week 36 and week 48 
 
To characterize the pharmacokinetic (PK) 
properties of olpasiran 
 
PK parameters for olpasiran including, but 
not limited to, maximum observed 
concentration (Cmax), and the area under 
the concentration time curve (AUC) 
Estimands for Secondary Endpoints 
The estimands for the secondary endpoints Lp(a), LDL-C, and ApoB are the differences 
between each olpasiran group and placebo in the mean percent change from baseline in: 
 
Lp(a) at week 48 
 
LDL-C at week 36 
 
LDL-C at week 48 
 
ApoB at week 36 
 
ApoB at week 48 
For adults with atherosclerotic cardiovascular disease and elevated Lp(a) who are randomized 
and received at least 1 dose of investigational product, regardless of discontinuation of 
investigational product and excluded medication(s) taken during the study. 
Safety 
 
To evaluate the safety and tolerability of 
olpasiran SC Q12W compared with 
placebo in subjects with elevated Lp(a) 
 
Treatment emergent adverse events 
 
Clinically significant safety laboratory 
values and vital signs at each scheduled 
visit 
Overall Design 
This is a phase 2, double-blind, randomized, placebo-controlled, multicenter, dose 
finding study to evaluate efficacy, safety, and tolerability of olpasiran on Lp(a) compared 
to placebo in subjects with atherosclerotic cardiovascular disease and with elevated 
Lp(a).   
Subjects will be randomized in a 1:1:1:1:1 ratio, with 4 arms being treated with olpasiran 
and 1 arm with placebo (some olpasiran arms will include placebo to maintain blind). 
The randomization will be stratified by screening Lp(a)  200 nmol/L vs.  200 nmol/L 
and by region (Japan vs. Non-Japan).  
The study treatment period is 48 weeks with doses at day 1, week 12, week 24, and 
week 36.  After week 48 there will be an extended safety follow-up without further dosing 
with investigational product for a minimum of 24 weeks.  Subjects will remain on 
standard of care (including stable lipid-altering therapy) per their local guidelines during 
the treatment period and extended safety follow-up period. 
Number of Subjects 
Approximately 290 subjects will be enrolled in the study, with approximately 58 subjects 
per treatment arm. 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 10 of 99 
CONFIDENTIAL  
 
 
Summary of Subject Eligibility Criteria 
A summary of eligible criteria for subjects to be included in the study are: 
Male or female adults age 18 to 80 years old, fasting Lp(a)  150 nmol/L during 
screening, atherosclerotic cardiovascular disease, and subjects receiving lipid-altering 
therapy (not required to participate in the study), must remain on stable dose.  
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Subjects will be randomized in a 1:1:1:1:1 ratio to 1 of the following 5 treatment groups: 
 
Group 1:  10 mg Q12W 
 
Group 2:  75 mg Q12W  
 
Group 3:  225 mg Q12W  
 
Group 4:  225 mg Q24W 
 
Group 5:  Placebo Q12W 
Procedures 
After providing informed consent, eligible subjects will undergo the following 
assessments during this study:  physical examination, neurological examination, 
physical measurements (height, weight, waist circumference) vital signs (blood pressure 
and heart rate),electrocardiogram, laboratory assessments (including serum pregnancy 
test, if applicable, serum Lp(a), lipids and fasting glucose, very low-density lipoprotein, 
coagulation, hematology, hemoglobin A1C, chemistry, high sensitivity C-reactive protein 
(hs-CRP), estimated glomerular filtration rate (eGFR), urinalysis, anti-olpasiran antibody 
test, biomarker, pharmacokinetic (PK) assessments, and a PROMIS (patient-reported 
outcomes measurement information system) general health assessment.  Reporting of 
adverse events, serious adverse events, and cases of pregnancy and lactation exposure 
will be performed as described in Section 8.2.4. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Table 1-1. 
Statistical Considerations 
All categorical variables will be summarized using the number and percent of subjects 
and all continuous variables will be summarized using mean, standard error or standard 
deviation, median, minimum, maximum, and number of subjects with observations. 
An interim analysis will be performed when approximately 240 subjects have had the 
opportunity to complete the week 24 assessments or have early terminated.  At that 
point, approximately 120 subjects may have had the opportunity to complete the 
week 36 assessments or have early terminated. 
Primary analysis will be performed when all randomized subjects have had the 
opportunity to complete the week 36 assessments or have early terminated.   
End of Treatment Period analysis will be performed when all randomized subjects have 
had the opportunity to complete week 48 assessments or have early terminated. 
Final analysis will be performed when all randomized subjects either complete the 
extended safety follow-up and ended the study or early terminate from the study. 
The primary endpoint (percent change from baseline in Lp(a) at week 36) will be 
compared between groups using repeated measures linear effects model including 
terms of treatment group, stratification factor, scheduled visit, and the interaction of 
treatment with scheduled visit.  Hochberg procedure will be used to control the type I 


Product:  Olpasiran 
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Page 11 of 99 
CONFIDENTIAL  
 
 
error for multiple comparisons between active and placebo arms for the primary 
endpoint.  The secondary endpoints percent change from baseline in Lp(a) at week 48, 
in ApoB and LDL-C at week 36 and 48 will be analyzed similarly as the primary 
endpoint.  Safety endpoints will be summarized descriptively. 
Baseline Lp(a) is defined as the mean of the two most recent non-missing Lp(a) values 
measured through central lab prior to or on study day 1.  If for any reason only 1 value is 
available then that value will be used as baseline. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
The null hypothesis is that there is no difference between olpasiran and placebo in 
percent change from baseline in Lp(a) at week 36 in subjects with atherosclerotic 
cardiovascular disease and with elevated Lp(a). 
 
Sponsor Name: 
 Amgen Inc. 
 


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1.2 
Study Schema 
Figure 1-1.  Study Schema 
End of Study (EOS)
Conducted for a 
minimum of           
24 weeks
D1
W12
W24
W36
W48
Screening Period:
≤ 4 weeks
Screening
Extended Safety 
Follow-up
(No dosing)
Group 1: AMG 890 10 mg Q12W SC 
(n = 58)
Group 2: AMG 890 75 mg Q12W SC 
(n = 58)
Group 3: AMG 890 225 mg Q12W SC 
(n = 58)
Group 4: AMG 890 225 mg Q24W SC 
(n = 58)
Group 5: Placebo Q12W SC (n = 58)
Randomization 1:1:1:1:1
Dosing
 
D  day; EOS  End of Study; Q12W  once every 12 weeks; Q24W  once every 24 weeks; SC  subcutaneous; W  week 


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1.3 
Schedule of Activities (SoA) 
Table 1-1.  Schedule of Activities (Screening Through Week 24) 
PROCEDURE 
Screening 
( 28 days 
before 
day 1) 
Treatment Period:  Screening to Week 24 
(Duration of 48 weeks)a 
Day 1 
D2 
W4 
W8 
W12 
W16 
W20 
W24 
W24 
Pre-
dose 
1 
hr 
3 
hr 
Pre-
dose 
1 
hr 
Phone 
callb 
Pre-
dose 
 1 
hr 
3 
hr 
Phone 
callb 
 2 
days 
 3 days 
 3 days 
 1 day 
 3 days 
 3 days 
 1 day 
GENERAL AND SAFETY ASSESSMENTS 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical, neurological, and muscular 
examination 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Physical measurements (body 
weight, height, waist circumference) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (single) 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Survival statusc  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse eventsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization (after eligibility 
confirmed)  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LABORATORY ASSESSMENTS 
Serum pregnancy test (females of 
childbearing potential only)e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (females of 
childbearing potential only)e 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Lipid Panel and Lp(a)f 
X 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
 
 
 
Fasting glucose 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Apolipoprotein A1 and 
Apolipoprotein Bf 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Page 1 of 4 


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Footnotes and abbreviations defined on last page of this table. 
Table 1-1.  Schedule of Activities (Screening Through Week 24) 
PROCEDURE 
Screening 
( 28 days 
before 
day 1) 
Treatment Period:  Screening to Week 24 
(Duration of 48 weeks)a 
Day 1 
D2 
W4 
W8 
W12 
W16 
W20 
W24 
W24 
Pre-
dose 
1 
hr 
3 
hr 
Pre-
dose 
1 
hr 
Phone 
callb 
Pre-
dose 
 1 
hr 
3 
hr 
Phone callb 
 2 
days 
 3 days 
 3 days 
 1 day 
 3 days 
 3 days 
 1 day 
LABORATORY ASSESSMENTS CONTINUED 
Coagulation 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Hematology 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Hemoglobin A1C 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Chemistry including hs-CRPf 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
eGFR 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
Anti-olpasiran-antibody 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
BIOMARKER ASSESSMENTS 
hs-IL-6f  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Discovery (eg, 
OxPL/ApoB and Lp(a) 
isoform) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker Development 
(optional)g  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(OPTIONAL) PHARMACOGENETIC ASSESSMENTS 
Pharmacogenetic 
Developmenth 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PHARMACOKINETIC ASSESSMENTS 
Olpasiran serum PKi 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
X 
X 
X 
 
CLINICAL OUTCOME ASSESSMENTS 
PROMIS General Health 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
STUDY TREATMENT 
Olpasiran or placebo 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Page 2 of 4 
Footnotes and abbreviations defined on last page of this table. 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 15 of 99 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities (Week 28 Through End of Study) 
PROCEDURE 
Treatment Period:  Week 28 to Week 48 
(Duration of 48 weeks)a 
Extended Safety  
Follow-upk 
End of Study 
W28 
W32 
W36 
W36 
W40 
W44 
W48 
W60 
 W72l 
Pre-
dose 
1 hr 
3 hr 
Phone 
callb 
 3 days 
 1 day 
 3 days 
 7 days 
 
GENERAL AND SAFETY ASSESSMENTS 
ECG (single) 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Physical, neurological, and 
muscular examination  
 
 
X 
 
 
 
 
 
X 
 
X 
Physical measurement (weight 
only) 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs 
 
 
X 
 
 
 
 
 
X 
 
X 
Survival statusc 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse eventsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant therapies review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Urine Pregnancy Test (females of 
childbearing potential only)e 
 
 
X 
 
 
 
 
 
X 
 
X 
Lipid Panel and Lp(a)f 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Fasting glucose 
 
 
X 
 
 
 
 
 
X 
 
X 
Apolipoprotein A1 and 
Apolipoprotein Bf 
 
 
X 
 
 
 
 
 
X 
 
X 
Coagulation 
 
 
X 
 
 
 
 
 
X 
 
X 
Hematology 
 
 
X 
 
 
 
 
 
X 
 
X 
Hemoglobin A1C 
 
 
X 
 
 
 
 
 
X 
 
X 
Chemistry including hs-CRPf 
 
 
X 
 
 
 
 
 
X 
 
X 
eGFR 
 
 
X 
 
 
 
 
 
X 
 
X 
Urinalysis 
 
 
X 
 
 
 
 
 
X 
 
X 
Anti-olpasiran-antibody 
 
 
X 
 
 
 
 
 
X 
 
X 
BIOMARKER ASSESSMENTS 
hs-IL-6f  
 
 
X 
 
 
 
 
 
X 
 
X 
Biomarker Discovery (eg, 
OxPL/ApoB and Lp(a) isoform) 
 
 
X 
 
 
 
 
 
X 
 
X 
Biomarker Development (optional)g 
 
 
X 
 
 
 
 
 
X 
 
X 
Page 3 of 4 
Footnotes and abbreviations defined on last page of this table. 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 16 of 99 
CONFIDENTIAL  
 
 
Table 1-1.  Schedule of Activities (Week 28 Through End of Study) 
PROCEDURE 
Treatment Period:  Week 28 to Week 48 
(Duration of 48 weeks)a 
Extended Safety  
Follow-upk 
End of Study 
W28 
W32 
W36 
W36 
W40 
W44 
W48 
W60 
 W72l 
Pre-
dose 
1 hr 
3 hr 
Phone 
callb 
 3 days 
 1 day 
 3 days  
 7 days  
 
PHARMACOKINETIC ASSESSMENTS 
Olpasiran serum PKi 
X 
 
X 
X 
X 
 
X 
 
X 
 
(X)j 
CLINICAL OUTCOME ASSESSMENTS 
PROMIS General Health 
 
 
X 
 
 
 
 
 
X 
 
(X)j 
Exit Survey 
 
 
 
 
 
 
 
 
X 
 
(X)j 
STUDY TREATMENT 
Olpasiran or placebo 
 
 
X 
 
 
 
 
 
 
 
 
Page 4 of 4 
A1C  glycated hemoglobin; ECG  electrocardiogram; eGFR  estimated glomerular filtration rate; FSH  follicle-stimulating hormone; hs-CRP  high sensitivity  
C-reactive protein; hs-IL-6  high sensitivity interleukin 6; Lp(a)  Lipoprotein(a); OxPL/ApoB  oxidized phospholipids on apolipoprotein B 100; 
PK  pharmacokinetics; PROMIS  Patient-Reported Outcomes Measurement Information System; W  week 
a Clinical outcome assessments should always be performed first at study visits, with study treatment administration performed last, except for days when post-dose 
PK samples are collected (day 1, week 12, week 24, and week 36).  
b Safety Follow-up calls are scheduled at 1 day after weeks 12, 24, and 36 visits.   
c Survival status checks should be performed for any subject who withdraws consent, or subjects considered lost to follow-up, or subjects unwilling to 
continue schedule of assessments, to the extent permitted by local law.  Refer to Section 8.2.3.2 for additional details.   
d After end of study, if the investigator becomes aware of serious adverse events suspected to be related to investigational product, then these serious 
adverse events will be reported to Amgen.  Please refer to Section 8.2.4.1.3 for additional details.   
e Additional on-treatment pregnancy testing may be performed at the investigator’s discretion if there is suspicion that a female subject is pregnant or per local laws and 
regulations.  Urine pregnancy test can be completed by study staff or local laboratory.   
f Blinded laboratory results:  Lp(a), lipid panel, hs-CRP, hs-IL-6, ApoA1, and ApoB laboratory result will be provided to sites at Screening and Day 1, but will be blinded 
after Day 1.   
g Biomarker development samples will be obtained from the biomarker discovery blood draw, for subjects who consent. 
h Optional pharmacogenomic sample will be derived from the biomarker plasma draw.  
i Additional PK samples will be collected in a subset of subjects (N  approximately 75) who consent to the optional PK sub-study.  Refer to Table 1-2 below for 
additional time points required for these subjects. 
j Collected at the end of study visit if this visit occurs prior to week 48. 
k After week 48 there will be an extended safety follow-up without further dosing with investigational product for a minimum of 24 weeks.  
l Per Protocol Amendment 2, some subjects will have an End of Study visit after week 72.   
 


Product:  Olpasiran 
Protocol Number:  20180109 
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Table 1-2.  Schedule of Activities-PK Sub-study 
PROCEDURE 
Screening 
Week 1 
(Dose 1) 
Week 24 
(Dose 2 [Q24W], Dose 3 [Q12W]) 
6 to 12 hrs 
post-dose 
24 to 72 hrs 
post-dose 
6 hr to 12 hrs 
post dose 
24 hrs to 72 hrs 
post dose 
GENERAL AND SAFETY ASSESSMENTS 
PK Sub-study Informed Consent 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
Serious adverse eventsa 
X 
X 
X 
X 
X 
Concomitant therapies review 
 
X 
X 
X 
X 
PHARMACOKINETIC ASSESSMENTS 
Olpasiran serum PKb 
 
X 
X 
X 
X 
 
Hr(s)  hour(s); PK  pharmacokinetics; Q12W  once every 12 weeks; Q24W  once every 24 weeks 
a After end of study, if the investigator becomes aware of serious adverse events suspected to be related to investigational product, then these serious 
adverse events will be reported to Amgen.  Please refer to Section 8.2.4.1.3 for additional details. 
b.PK sub-study subjects will also have the required PK samples drawn as part of the main study (refer to Table 1-1 for time points).  
 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
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2. 
Introduction 
2.1 
Study Rationale 
Study 20180109 is a double-blind, randomized, multicenter dose finding study in 
subjects with atherosclerotic cardiovascular disease and elevated lipoprotein(a) (Lp[a]).  
The primary objective is to test olpasiran administered subcutaneous (SC) once every 
12 weeks (Q12W) compared with placebo on percent change from baseline in Lp(a) 
after 36 weeks of treatment.  Additionally, an exploratory dose of 225 mg once every 
24 weeks (Q24W) will be evaluated.  The treatment period is 48-weeks, with the 
last dose of investigational product administered at week 36.  After the week 48 
treatment period there will be an extended safety follow-up for a minimum 
of 24 weeks.   
Olpasiran is being developed for the treatment of patients with atherosclerotic 
cardiovascular disease and elevated lipoprotein(a) (Lp[a]) to reduce the risk of 
cardiovascular events.  Lp(a) reductions of  80 from baseline are anticipated with 
olpasiran and it is expected that this level of reduction in Lp(a) may result in clinically 
meaningful cardiovascular benefit in patients with atherosclerotic cardiovascular disease 
(Kamstrup et al, 2009, Burgess et al, 2018, Lamina et al, 2019, Madsen et al, 2020).   
Available data from the initial cohorts of the first in human (FIH) study has shown the 
following: 
 
Olpasiran can effectively lower Lp(a) levels. 
 
Pharmacodynamic (PD) effects last up to at least 3 months. 
 
At single doses up to 225 mg (cohort 7), olpasiran was tolerated with no safety 
concerns identified as of day 225. 
The olpasiran target population is patients with atherosclerotic cardiovascular disease 
and significantly elevated Lp(a).  All patients will be receiving optimized standard of care 
for other cardiovascular risk factors, including elevated low-density lipoprotein 
cholesterol (LDL-C), but still be at risk for cardiovascular events from high Lp(a) levels. 
The Lp(a) cutoff of 150 nmol/L is based on the epidemiological data that is available 
showing that Lp(a)  125 nmol/L is considered elevated from the general population data 
(Averna et al, 2017; Nordestgaard and Langsted, 2016; Ohro-Melander, 2015; 
Leebmann et al, 2013).  In addition, based on the degree of absolute Lp(a) reduction 
necessary to demonstrate a corresponding effect on cardiovascular events, the enrolled 
population would need to have high baseline Lp(a).  Therefore, an enrollment criterion of 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 19 of 99 
CONFIDENTIAL  
 
 
Lp(a)  150 nmol/L would result in a study population with a median Lp(a) of 
approximately 200 nmol/L and allows evaluation of the effectiveness and safety of 
olpasiran in subjects with very high Lp(a). 
A recent Mendelian randomization study suggests that in individuals with very high 
baseline Lp(a) concentrations, reducing Lp(a) by 80 to 90 is expected to translate 
into a clinically meaningful reduction in the risk of cardiovascular events  
(Khan et al, 2017; Leebmann et al, 2013; Safarova et al, 2013, Burgess et al, 2018, 
Lamina et al, 2019, Madsen et al, 2020). 
2.2 
Background 
2.2.1 
Disease 
Despite significant advances in the identification and control of modifiable risk factors for 
cardiovascular disease, including smoking, hypertension, diabetes, and dyslipidemias, 
cardiovascular disease remains the leading cause of death and disability worldwide, 
accounting for approximately 31 of all deaths according to the World Health 
Organisation (WHO, 2014).  Furthermore, after a cardiovascular event, patients may 
suffer from both acute and long-term reductions in health-related quality of life, including 
diminished mobility and functionality, as well as anxiety, depression, fatigue, and sexual 
dysfunction (Bach et al, 2011; Schweikert et al, 2009; Brink et al, 2005; 
Simpson and Pilote, 2003; Mendes de Leon et al, 1998). 
While lipid-lowering therapy research has historically focused on LDL-C to reduce 
cardiovascular risk, epidemiologic evidence identifies elevated plasma Lp(a) as a strong 
independent risk factor for atherosclerotic cardiovascular disease (Kassner et al, 2015; 
Willeit et al, 2014; Kamstrup et al, 2013; Jacobson, 2013; Dubé et al, 2012; 
Emerging Risk Factors Collaboration, 2009; Kamstrup et al, 2009; Bennet et al, 2008; 
Kamstrup et al, 2008; Danik et al, 2006).  Elevated plasma Lp(a) levels have also been 
associated with atherosclerotic disease severity and progression (Kotani et al, 2017; 
Poller et al, 2015; Stather et al, 2014; Guler et al, 2013; Ronald et al, 2011; 
Gardener et al, 2009; Habib et al, 2009; Takagi et al, 2009; Schillinger et al, 2002). 
The physiological function of Lp(a) is unclear, but Lp(a) has been shown to have a 
pathogenic role in atherosclerosis and thrombosis formation 
(Nordestgaard and Langsted, 2016).  The connection between Lp(a) levels and coronary 
artery disease, myocardial infarction, stroke, peripheral vascular disease, and aortic 
valve stenosis has been described in several genetic and observational studies 


Product:  Olpasiran 
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Date:  02 May 2022 
Page 20 of 99 
CONFIDENTIAL  
 
 
(Schmidt et al, 2016).  It has been noted that this risk relationship is continuous and 
becomes proportionally more impactful with higher Lp(a) levels.  The association 
persists after correction for other lipid parameters (Emerging Risk Factors 
Collaboration, 2009). 
Elevated Lp(a) has varying definitions depending upon the population under study and 
the assay being used.  Some studies have estimated that 20 to 30 of the population 
have Lp(a)  50 mg/dL (Varvel et al, 2016; Nordestgaard et al, 2010).  The American 
College of Cardiology/American Heart Association (ACC/AHA) Cholesterol guidelines 
further state that  if a decision is made to measure Lp(a), an Lp(a)  50 mg/dL 
or   125 nmol/L, may be considered a risk enhancing factor (Grundy et al, 2019).  The 
National Lipid Association suggest that Lp(a)  50 mg/dL ( 100 nmol/L) be considered 
the elevated risk threshold (Wilson et al, 2019); the Canadian Cardiovascular Society 
states that levels  30 mg/dL are considered elevated (Anderson et al, 2016); and a 
study in the Chinese Han observed increasing risk at  17 mg/dL (Cui et al, 2018).  The 
prevalence of Lp(a)  50 mg/dL ( 125 nmol/L) varies by country of origin with an 
estimated 30 in Africa; 25 in South Asia; 20 in Europe, Oceania, and North 
America; 15 in South America; and 10 in Asia (Tsimikas et al, 2018).  The risk for the 
development of significant coronary artery disease appears to be increased with plasma 
Lp(a) levels as low as 30 mg/dL in European populations, and the risk of myocardial 
infarction is elevated by 2- to 3.5-fold in individuals with elevated Lp(a) levels 
(Norderstgaard and Langstedt, 2016; Kamstrup et al, 2009). 
The ESC/EAS dyslipiaemia guidelines state that Lp(a) measurement should be 
considered at least once in each adult’s lifetime (Mach et al, 2020).  American College of 
Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines state that 
Lp(a) is a modified form of LDL-C that appears to possess atherogenic potential.  
Indications for its measurement are a family history of premature atherosclerotic 
cardiovascular disease or personal history of atherosclerotic cardiovascular disease not 
explained by major risk factors (Grundy et al, 2019).  Recommendations for measuring 
Lp(a) levels in adults have also been added to guidelines or scientific statements from 
the Canadian Cardiovascular Society, the National Lipid Association, and HEART UK 
(Anderson et al, 2016; Wilson et al, 2019; Cegla et al, 2019).   
High plasma Lp(a) concentration is genetically defined, remains at stable levels, cannot 
be controlled by habit modifications (diet, exercise, or other environmental factors), and 
is not effectively controlled by any of the currently available lipid reducing medications.  
Currently, there are no approved therapies indicated to reduce the risk of cardiovascular 
events through reductions in Lp(a).  Approaches to lower Lp(a) include use of proprotein 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 21 of 99 
CONFIDENTIAL  
 
 
convertase subtilisin/kexin type 9 (PCSK9) inhibitors, niacin, or mipomersen 
(Santos et al, 2015; Yeang et al, 2015; Landray et al, 2014), which decrease Lp(a) 
moderately.  While lipoprotein apheresis is effective in lowering Lp(a), it is currently used 
only in a few countries with limited access (Julius, 2018).  In addition, it is an invasive, 
very expensive procedure requiring frequent visits, which makes it unfeasible as a long-
term treatment for subjects who need lifelong therapy (Khan et al, 2017; Roeseler et al, 
2016; Leebmann et al, 2013; Safarova et al, 2013). 
Therefore, novel agents that lower high Lp(a) concentrations are being investigated to 
confer additional protection against cardiovascular disease.  Although definitive evidence 
that the reduction in plasma Lp(a) will provide cardiovascular risk reduction is lacking, 
Mendelian randomization epidemiologic studies, lipoprotein apheresis cohort results, 
and experimental data suggest a causal role for elevated Lp(a) (Averna et al, 2017; 
Nordestgaard and Langsted, 2016; Ohro-Melander, 2015; Leebmann et al, 2013) and 
provide the rationale for exploring the therapeutic concept. 
2.2.2 
Amgen Investigational Product Background:  Olpasiran 
Small interfering (also called short interfering) RNA molecules (siRNA) are synthetic 
RNA duplexes that disrupt the expression of specific genes with complementary 
nucleotide sequences by degrading mRNA after transcription, preventing translation 
(Agrawal et al, 2003).  The serum pharmacokinetics in Amgen’s nonclinical program 
support fast clearance from the blood compartment and effective delivery to liver due to 
GalNAc conjugation via the asialoglycoprotein receptor (ASGPR). Olpasiran is a fully 
chemically modified siRNA, and is therefore, slowly degraded by endo- and 
exo-nucleases in the liver (Nair et al, 2017). 
Uptake of the siRNA into cells involves endocytosis and release from the endosome to 
the cytosol, a mechanism that is not currently well understood.  Once in the cytosol, the 
antisense (guiding) strand of the siRNA double strand is loaded into an RNA-induced 
silencing complex (RISC), while the other one is degraded.  The loaded RISC is then 
directed to an mRNA which has complementary sequence of the guide strand.  
Argonaute proteins present in RISC cleave the target mRNA, which is then further 
degraded by exonucleases.  Dissociation of the target mRNA strand from RISC after the 
cleavage allow more mRNA to be silenced, enabling continual degradation of target 
mRNA and leading to efficient and potent gene silencing (Agrawal et al, 2003).  Small 
interfering RNA molecules can also be targeted for uptake in select tissues via 
conjugation of the siRNA to high-affinity antibody or antibody fragments, nucleic acids, or 
receptor ligands to bind to cell surface receptors and to mediate cell-specific uptake.  


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 22 of 99 
CONFIDENTIAL  
 
 
Targeted uptake has the advantages of being effective at a lower dose and may confer 
reduced toxicity from uptake and knockdown in unintended tissues.  In particular, SC 
administration of siRNAs conjugated to trivalent N-acetylgalactosamine (GalNAc), which 
mediates hepatocyte uptake through the hepatocyte-restricted ASGPR in liver-targeted, 
durable gene knockdown (Wittrup and Lieberman, 2015). 
Olpasiran is an siRNA designed to target the mRNA transcribed from the LPA gene, 
which encodes apo(a) protein in liver cells.  Thus, olpasiran is able to specifically knock 
down hepatic Lp(a) production.  The siRNA molecule is formed by the hybridization of 
two partially complementary single-strands of RNA with 21 consecutive complementary 
base pairs. 
Pharmacology 
Amgen’s nonclinical program showed that olpasiran can achieve a sustained  80 
reduction in plasma Lp(a).  The studies supporting this conclusion included efficacy data 
collected from transgenic mice and cynomolgus monkeys demonstrating that Lp(a) 
levels can be specifically targeted with olpasiran to inhibit apo(a) translation.   
A detailed description of the chemistry, pharmacology, efficacy, and safety of olpasiran 
is provided in the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
Elevated plasma Lp(a) has been identified as a strong independent risk factor for the 
development and progression of atherosclerotic disease (Ellis et al, 2017).  Lp(a) has 
been associated with increased risk for myocardial infarction, aortic valve stenosis 
development, carotid artery stenosis and abdominal aorta aneurism progression.  High 
plasma Lp(a) concentration is genetically defined, cannot be controlled by healthy habit 
modifications and 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 
cardiovascular disease.  Although definitive evidence that the reduction in plasma Lp(a) 
will provide cardiovascular risk reduction is not yet available, mendelian randomization 
epidemiologic studies, plasma apheresis cohort results, and experimental data suggest 
a causal role for elevated Lp(a) (Averna et al, 2017; Nordestgaard and Langsted, 2016; 
Ohro-Melander, 2015) and provide the rationale for exploring the therapeutic concept.   
There are no identified risks for olpasiran and potential risks are limited to liver enzyme 
elevation and hypersensitivity reactions.  Other events of interest for olpasiran, that have 
not been borne out either by the non-clinical or available clinical data, but that are based 


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Protocol Number:  20180109 
Date:  02 May 2022 
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CONFIDENTIAL  
 
 
on the siRNA/oligotherapeutics platform include:  effects on platelets and coagulation, 
immune inflammatory response, 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 (Paige et al, 2017; Ye et al, 2014).  These 
risks have not been borne out by either the non-clinical data or clinical data to date for 
olpasiran.   
All study subjects will be closely monitored and frequently assessed for adverse events 
throughout the study.  The laboratory safety monitoring includes evaluation of routine 
chemistry (including liver function tests and renal function), hematology, HbA1c, and 
coagulation assessments.  Potential anaphylactic reactions will be assessed by the 
investigator based on Sampson clinical criteria for diagnosing anaphylaxis 
(Sampson et al, 2006) and reported accordingly on the adverse event electronic case 
report form (eCRF).  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.  Bioanalytical testing for anti-olpasiran antibodies will be conducted only if 
there are unexpected PD findings or a safety signal in this study or future studies that 
warrants further investigation. 
Amgen has been closely monitoring the evolving Coronavirus disease-19 (COVID-19) 
pandemic around the globe.  As part of this effort, Amgen has performed a rigorous 
assessment, in discussion with study investigators, considering the study design, patient 
safety, public health risk, risk-benefit ratio, as well as the burden on country healthcare 
systems.  Given the safety concerns around COVID-19 and the associated risk to 
maintaining normal clinical study operations, Amgen is making decisions on a study-by-
study and country-by-country basis to minimize risk to patients and avoid undue burden 
on healthcare facilities and accordingly, is allowing enrollment to continue in studies 
where the potential for significant benefit in a serious or life-threatening condition exists 
and where site resources allow new patients to be safely enrolled and appropriately 
monitored.  
Potential risks associated with study participation, in particular with added challenges 
due to COVID-19, may be outweighed by anticipated benefits associated with the study 
treatment. 
Patients who display symptoms consistent with COVID-19 infections or who have tested 
positive for COVID-19 should urgently contact their site medical monitor to ensure 
appropriate care as well as documentation and management of study activities. 


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Protocol Number:  20180109 
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Amgen considers that it is important to continue the proposed development of olpasiran 
in this study in order to advance potential therapy options for patients as rapidly as 
possible, while balancing this with appropriate measures to monitor and mitigate the 
potential impact of COVID-19.  
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure for further data on olpasiran. 
3. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of olpasiran 
administered subcutaneous (SC) once 
every 12 weeks (Q12W) compared with 
placebo, on percent change from baseline 
in lipoprotein(a) (Lp[a]) after 36 weeks of 
treatment 
 
Percent change in Lp(a) from baseline at 
week 36 
Primary Estimand 
The primary estimand consists of: 
 
The target population, which is adults with atherosclerotic cardiovascular disease and 
elevated Lp(a)  
 
The primary variable, which is percent change from baseline in Lp(a) at week 36 
 
The intercurrent events which are the discontinuation of investigational product and 
excluded medication(s) taken during study.  For the primary estimand, the treatment effect 
will be estimated in subjects who are randomized and received at least 1 dose of 
investigational product regardless of the occurrence of these intercurrent events 
 
The summary measure, which is the difference between olpasiran and placebo in the 
mean percent change from baseline in Lp(a) at week 36 
 
The treatments to be compared are each olpasiran group versus placebo 
The primary estimand is the difference between each olpasiran group and placebo in the mean 
percent change from baseline in Lp(a) at week 36 in adults with atherosclerotic cardiovascular 
disease and elevated Lp(a) who are randomized and received at least 1 dose of investigational 
product, regardless of discontinuation of investigational product and excluded medication(s) 
taken during the study. 
Objectives 
Endpoints 
Secondary 
 
To evaluate the effect of olpasiran 
administered SC Q12W compared with 
placebo, on percent change from baseline 
in: 
- 
Lp(a) after 48 weeks of treatment 
- 
Low-density lipoprotein cholesterol 
(LDL-C) after 36 and 48 weeks of 
treatment 
- 
Apolipoprotein(B) (ApoB) after 36 and 
48 weeks of treatment 
 
Percentage change from baseline in:   
- 
Lp(a) at week 48 
- 
LDL-C at week 36 and week 48 
- 
ApoB at week 36 and week 48 
 
To characterize the pharmacokinetic (PK) 
properties of olpasiran 
 
PK parameters for olpasiran including, but 
not limited to, maximum observed 
concentration (Cmax), and the area under 
the concentration time curve (AUC) 
Estimands for Secondary Endpoints 


Product:  Olpasiran 
Protocol Number:  20180109 
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The estimands for the secondary endpoints in Lp(a), LDL-C, and ApoB are the differences 
between each olpasiran group and placebo in the mean percent change from baseline in: 
 
Lp(a) at week 48 
 
LDL-C at week 36 
 
LDL-C at week 48 
 
ApoB at week 36 
 
ApoB at week 48 
For adults with atherosclerotic cardiovascular disease and elevated Lp(a) who are randomized 
and received at least 1 dose of investigational product, regardless of discontinuation of 
investigational product and excluded medication(s) taken during the study. 
 
Exploratory 
 
To evaluate the effect of olpasiran 
administered SC Q12W compared with 
placebo, on: 
- 
percent change from baseline in Lp(a) 
- 
percent change from baseline in  
LDL-C 
- 
percent change from baseline in 
ApoB 
- 
achievement of Lp(a)  125 nmol/L 
- 
achievement of Lp(a)  100 nmol/L 
- 
achievement of Lp(a)  75 nmol/L 
- 
achievement of Lp(a)  50 nmol/L 
 
Percent change from baseline at each 
scheduled visit, except weeks 36 and 48, 
in:   
- 
Lp(a) 
- 
LDL-C 
- 
ApoB 
 
Achievement at each scheduled visit of 
the following: 
- 
Lp(a)  125 nmol/L 
- 
Lp(a)  100 nmol/L 
- 
Lp(a)  75 nmol/L 
- 
Lp(a)  50 nmol/L  
 
To evaluate the effect of olpasiran 
administered SC once every 24 weeks 
(Q24W) compared with olpasiran 
administered SC Q12W and placebo, on: 
- 
percent change from baseline in Lp(a) 
- 
percent change from baseline in LDL-
C 
- 
percent change from baseline in 
ApoB 
- 
achievement of Lp(a)  125 nmol/L 
- 
achievement of Lp(a)  100 nmol/L 
- 
achievement of Lp(a)  75 nmol/L 
- 
achievement of Lp(a)  50 nmol/L 
For the olpasiran SC Q24W group: 
 
Percent change from baseline at each 
scheduled visit, in:   
- 
Lp(a) 
- 
LDL-C 
- 
ApoB 
 
Achievement at each scheduled visit of 
the following: 
- 
Lp(a)  125 nmol/L 
- 
Lp(a)  100 nmol/L 
- 
Lp(a)  75 nmol/L 
- 
Lp(a)  50 nmol/L 
 
Objectives 
Endpoints 
Exploratory 
 
To estimate cardiovascular event rates in 
subjects treated with olpasiran, including 
aggregated exploratory analyses across 
the olpasiran program 
 
Adjudicated events 
 
To describe the effect of olpasiran of 
quality of life (QoL) measures as 
assessed using the PROMIS Global 
Health 
 
Change from baseline in PROMIS Global 
Health measures at each scheduled visit 
 
To evaluate the effect of olpasiran 
administered SC on inflammatory 
biomarkers  
 
Change from baseline at week 48 in: 
- 
high sensitivity C-reactive protein 
(hs-CRP) 
- 
high sensitivity Interleukin 6 
(hs-IL-6)  


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 
To assess the anti-olpasiran antibody 
response 
 
Anti-olpasiran antibody formation, if tested 
Safety 
 
To evaluate the safety and tolerability of 
olpasiran administered SC compared with 
placebo in subjects with elevated Lp(a) 
 
Treatment emergent adverse events 
 
Clinically significant safety laboratory 
values and vital signs at each scheduled 
visit 
4. 
Study Design 
4.1 
Overall Design 
This is a phase 2, double-blind, randomized, placebo-controlled, multicenter, dose 
finding study to evaluate efficacy, safety, and tolerability of olpasiran on Lp(a) compared 
to placebo in subjects with atherosclerotic cardiovascular disease and with elevated 
Lp(a).   
Subjects will be randomized in a 1:1:1:1:1 ratio to 1 of the following 5 treatment groups 
(some olpasiran arms will include placebo to maintain blind): 
 
Group 1:  10 mg Q12W 
 
Group 2:  75 mg Q12W 
 
Group 3:  225 mg Q12W 
 
Group 4:  225 mg Q24W 
 
Group 5:  Placebo Q12W 
The randomization will be stratified by screening Lp(a)  200 vs.  200 nmol/L and by 
region (Japan vs. Non-Japan).  
The study treatment period is 48 weeks with doses at day 1, week 12, week 24, and 
week 36.  After week 48 there is an extended safety follow-up without further dosing with 
investigational product for a minimum of 24 weeks.  Subjects will remain on standard of 
care (including stable lipid-altering therapy) per their local guidelines during the 
treatment period and extended safety follow-up period. 
An interim analysis will be performed when approximately 240 subjects have had the 
opportunity to complete the week 24 assessments or have early terminated.  At that 
point, approximately 120 subjects may have had the opportunity to complete the 
week 36 assessments or have early terminated.   
The interim analysis results will be used to support dose selection for a phase 3 
registrational study and trigger early planning for the phase 3 program.  In addition, the 
safety and efficacy results may be used in company internal discussions and external 


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interactions with regulatory agencies.  The study continues regardless of the 
administrative interim results.   
The primary analysis will occur when all randomized subjects have had the opportunity 
to complete the week 36 assessments or have early terminated.  The end of treatment 
period analysis will occur when all subjects have had the opportunity to complete the 
week 48 assessments or have early terminated.  Final analysis will occur after the 
last subject either completes the extended safety follow-up and has ended the study or 
has early terminated from the study. 
Team members that remain directly involved with the conduct of the study, investigators, 
and subjects will not receive results of the interim and primary analyses and will remain 
blinded until formally unblinded. 
The study will be formally unblinded to Amgen or Amgen designees after 
treatment period is ended, database is locked, and the snapshot is taken for end 
of treatment analysis.  Sites and subjects will not have access to unblinded 
information until the study is formally ended at EOS (as defined in Section 4.4.1), 
database is locked, and the snapshot is taken for final analysis. 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 
4.2 
Number of Subjects 
Approximately 290 subjects will be enrolled in the study, with approximately 58 subjects 
per treatment arm. 
Subjects in this clinical investigation shall be referred to as “subjects”.  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
4.2.2 
Number of Sites 
Approximately 36 investigative sites in United States, Canada, Europe, Japan, and 
Australia will be included in the study.  Sites that do not enroll subjects within 3 months 
of site initiation may be closed. 
4.3 
Justification for Investigational Product Dose 
Investigational product dose ranges were selected based on available data from phase 1 
Study 20170544 and the additional following considerations: 


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 
General understanding of safety regarding oligonucleotide-based therapeutics, ie, 
antisense oligonucleotide and siRNA therapeutics and their mechanism of action. 
 
Lp(a) reductions of  80 from baseline are being targeted because this level of 
reduction is anticipated to be required to observe cardiovascular benefit in patients 
with atherosclerotic cardiovascular disease. 
 
Olpasiran PK/PD modelling and simulation results based on data from 
Study 20170544 indicate that:  
 
A low dose of 10 mg administered Q12W will provide target ( 80) Lp(a) 
suppression in approximately half (42) of subjects with baseline 
Lp(a)  150 nmol/L by month 12.  Despite median Lp(a)  reductions from 
baseline of approximately 77 at months 6 and 12, only 41 and 64 of these 
subjects will achieve Lp(a) values of  50 nmol/L by month 12.  Therefore, the 
10 mg dose will provide additional PK and Lp(a) data within the lower dynamic 
range of the olpasiran exposure-response relationship and help support selection 
of the phase 3 dose in the target patient population. 
 
An intermediate dose of 75 mg administered Q12W was selected as it is 
anticipated to provide target (80) Lp(a) suppression from baseline within 2 to 
3 doses in the majority (94) of subjects by month 12.  Furthermore, 
approximately 90 of subjects are expected to achieve Lp(a)  50 nmol/L, which 
may support selection of this dose for phase 3 evaluation. 
 
A high dose of 225 mg Q12W is expected to provide a similar degree of Lp(a) 
suppression ( 80) in the majority of subjects (98), but with a greater 
proportion of subjects (96) achieving reductions of Lp(a)  50 nmol/L by 
month 12.  Given that the magnitude and durability of Lp(a) suppression appears 
to increase with dose, the 225 mg dose will also provide greater magnitudes of 
Lp(a) suppression with multiple dosing. 
 
A frequency of Q12W dosing was selected for the above doses based on the 
durability of Lp(a) response over time and to ensure target suppression levels are 
maintained throughout the entire dosing interval in the majority ( 90) of subjects 
with elevated Lp(a) levels  150 nmol/L. 
 
A dose of 225 mg administered Q24W will also be evaluated in this study to explore 
opportunities for less frequent (Q24W) dosing in this patient population and to 
assess Lp(a) lowering impact throughout the 6-month dosing interval in a multiple 
dose setting.  Modeling and simulation data suggest that 225 mg Q24W dosing will 
result in median Lp(a) reductions from baseline of 88 and with approximately 74 
of subjects achieving Lp(a) levels  50 nmol/L. 
4.4 
End of Study 
4.4.1 
End of Study Definition 
Primary Completion:  The primary completion date is defined as the date when the 
last subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s). 
The primary completion date is the date when the last subject has completed the 
assessments for week 36. 


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If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study (EOS) date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study  
(ie, last subject last visit), following any additional parts in the study (eg, extended safety 
follow-up, additional antibody testing), as applicable. 
4.4.2 
Study Duration for Subjects 
The anticipated study duration will be approximately 76 weeks.  This includes a 4-week 
screening window, a treatment period of 48 weeks, followed by an extended safety 
follow-up of a minimum of 24 weeks. 
4.5 
Patient Input on Study Design 
The team conducted Facilitated Reviews and Patient Panels with patients with high 
Lp(a) and with caregivers to obtain the patient voice to incorporate into the protocol and 
study conduct. 
5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).  This log may be completed and updated via an Interactive Response 
Technology. 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
101 
Subject has provided informed consent prior to initiation of any study specific 
activities/procedures. 
102 
Age 18 to 80 years 
103 
Fasting Lp(a)  150 nmol/L during screening by central laboratory (approximately 
corresponds to  60 mg/dL: note that molarity determines eligibility) 


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104 
Atherosclerotic cardiovascular disease based on 1 of the following: 
 
History of coronary revascularization with percutaneous coronary intervention 
(PCI) or coronary artery bypass grafting (CABG) 
 
Diagnosis of coronary artery disease with or without prior myocardial 
infarction 
 
Diagnosis of atherosclerotic cerebrovascular disease 
 
Diagnosis of peripheral arterial disease 
105 
For subjects receiving lipid-altering therapy (not required to participate in this 
study), lipid-altering therapy, including statin dose, must remain stable per local 
guidelines for  4 weeks prior to and during screening 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
Disease Related 
201 
Severe renal dysfunction, defined as an estimated glomerular filtration rate 
(eGFR)  30 mL/min/1.73 m2 during screening 
202 
History or clinical evidence of active liver disease or hepatic dysfunction, defined 
as aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT)  3 x upper limit of normal (ULN), or total bilirubin (TBL)  2 x ULN during 
screening 
203 
Inherited or other bleeding disorders 
204 
Recent major cardiovascular event (myocardial infarction, unstable angina, PCI, 
CABG, or stroke) within 6 months prior to day 1 
205 
Planned cardiac surgery, PCI or carotid stenting, or planned major non-cardiac 
surgery during the study period 
Other Medical Conditions 
206 
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, 
breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 
5 years prior to day 1 
207 
Moderate to severe heart failure (New York Heart Association (NYHA) Functional 
Classification III or IV at day 1) or last known left ventricular ejection fraction 
 30 
208 
Uncontrolled cardiac arrhythmia defined as recurrent and highly symptomatic 
ventricular tachycardia, atrial fibrillation with rapid ventricular response, or 
supraventricular tachycardia that are not controlled by medications, in the past 
3 months prior to day 1 
209 
Uncontrolled hypertension at day 1, defined as an average systolic blood 
pressure of  160 mmHg or an average diastolic blood pressure of  100 mmHg 
at rest  
210 
Fasting triglycerides  400 mg/dL (4.5 mmol/L) during screening   


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211 
Type 1 diabetes or poorly controlled (HbA1c  8.5) type 2 diabetes mellitus as 
determined by central laboratory at screening 
212 
Known active infection or major hematologic, renal, metabolic, gastrointestinal or 
endocrine dysfunction, or a chronic disease or infection (eg, HIV) that is not 
currently stable and appropriately managed in the judgment of the investigator at 
day 1 
Prior/Concomitant Therapy 
213 
Previously received treatment with antisense oligonucleotides (ASO), siRNA 
therapies (eg, inclisiran), or any experimental therapy targeting Lp(a) 
215 
Currently undergoing lipid apheresis or  3 months since last apheresis treatment 
at day 1 
216 
Subject has taken a cholesterol ester transfer protein inhibitor (eg, anacetrapib, 
dalcetrapib, evacetrapib) or lomitapide in the last 12 months prior to day 1 
226 
Currently receiving, or  3 months at day 1 since receiving  200 mg/day Niacin 
Prior/Concurrent Clinical Study Experience 
217 
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days since ending treatment on another investigational device or 
drug study(ies).  Other investigational procedures while participating in this study 
are excluded. 
218 
Use of any herbal medicines, vitamins or supplements known to affect lipid 
metabolism (eg, fish oil  4000 mg/day, red yeast rice extract), within 30 days 
prior to day 1 
Other Exclusions 
219 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 90 days after the last dose of 
investigational product.   
220 
Female subjects of childbearing potential unwilling to use a highly effective 
method of contraception during treatment and for an additional 90 days after the 
last dose of investigational product.  Refer to Section 11.5 for additional 
contraceptive information. 
221 
Female subjects of childbearing potential with a positive serum pregnancy test 
assessed at Screening or positive urine pregnancy test on day 1.   
222 
Subject has known sensitivity to any of the products to be administered during 
dosing. 
223 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, Clinical 
Outcome Assessments) to the best of the subject and investigator’s knowledge. 
224 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion.  


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5.3 
Lifestyle Considerations 
5.3.1 
Activity 
Subjects will abstain from strenuous exercise for 48 hours before each blood collection 
for clinical laboratory tests.   
5.4 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form (ICF), and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent before commencement of study-specific procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (after signing the 
informed consent) receives a unique subject identification number before any 
study-related activities/procedures are performed.  The subject identification number will 
be assigned by IRT.  This number will be used to identify the subject throughout the 
clinical study and must be used on all study documentation related to that subject. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.  This number will not necessarily be the same as the randomization number 
assigned for the study. 
5.5 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, medical history, prior therapies, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened 1 time.  Refer to Section 8.1.1. 


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5.6 
Washout Period/Run-in Period/Invasive Procedure(s) 
Washout Period, /Run-in period, and Invasive Procedure(s) are not applicable to this 
study. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), non-investigational 
product(s), placebo, or medical device(s) intended to be administered to a study subject 
according to the study protocol. 
Note that in several countries, investigational product and non-investigational product 
are referred to as investigational medicinal product and non-investigational medicinal 
product, respectively. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of each treatment shown in Table 6-1 below. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 
 


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Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a,b 
olpasiran 
Placebo 
Dosage Formulation 
The final container is a 2R vial size.  Type I glass vial 
and contains 1 mL deliverable volume of olpasiran 
(1 mL vial target fill volume). 
Placebo will be presented in identical containers, and 
stored/packaged the same as olpasiran 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
 
Treatment Group 1:  10 mg Q12W 
 
Treatment Group 2:  75 mg Q12W 
 
Treatment Group 3:  225 mg Q12W 
 
Treatment Group 4:  225 mg Q24W 
 
Treatment Group 5:  Placebo Q12W 
Route of Administration 
SC injection 
Accountability 
The volume, start date, start time, injection site, and box number(s) of investigational product are to be recorded 
on each subject’s CRF. 
Dosing Instructions 
Study treatment are to be administered at study visits by authorized investigational site study staff per the 
investigational product instructional manual (IPIM).  Olpasiran administration should be completed after all study 
visit activities including pre-dose PK blood draws have been performed, but prior to the 1 hour and 3 hour 
post-dose PK measurements.  An observation period of 1-hour will occur after each injection of study treatment. 
CRF  case report form; PK  pharmacokinetic; Q12W  once every 12 weeks; Q24W  once every 24 weeks; SC  subcutaneous 
a Olpasiran will be manufactured and packaged by Amgen and distributed using Amgen clinical study drug distribution procedures. 
b In order to maintain blinding, placebo will administered to some olpasiran treatment groups, as applicable. 
 


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6.1.2 
Medical Devices 
A diagnostic test will be used to measure Lp(a) to select subjects for treatment based on 
subject samples collected prospectively during the study.  The diagnostic test is intended 
to measure Lp(a) in serum, as further described in Section 8.2.9.   
6.1.3 
Other Protocol-required Therapies 
Other protocol-required therapies are not applicable for this study.   
6.1.4 
Other Treatment Procedures 
No other treatment procedures are required for this study. 
6.1.5 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for distribution 
to market or clinic by either (1) Amgen or (2) distributors and partners for whom Amgen 
manufactures the material.   
This includes olpasiran/placebo provisioned and/or repackaged/modified by Amgen. 
Any product complaint(s) associated with an investigational product(s) 
(olpasiran/placebo), non-investigational products supplied by Amgen are to be 
reported. 
6.1.6 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments are not permitted during the study: 
 
Anti-sense Oligonucleotide therapies (ASO) 
 
Other small interfering Ribonucleic Acid (siRNA) therapies (eg, inclisiran) 
 
Niacin  200 mg/day 
 
Lipid apheresis 
 
Cholesterol ester transfer protein inhibitor (eg, anacetrapib, dalcetrapib, evacetrapib) 
 
Lomitapide 
 
any investigational therapies other than study provided IP 
 
any lipid-altering therapies not taken at the time of screening and enrollment 
If starting a new lipid-altering therapy is medically warranted during the trial, the subject 
should continue to receive IP; these situations should be discussed with the Amgen 
medical monitor as soon as possible.   


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All herbal supplements, vitamins, and nutritional supplements known to affect lipid 
metabolism (eg, fish oil  4000 mg/day, red yeast rice extract) should not be taken within 
30 days prior to dosing on day 1 and should not be used during the study, unless 
reviewed and approved by the investigator and Amgen Medical Monitor.  
Niacin  200 mg/day should not be taken within 3 months prior to day 1.  Written 
documentation of this review and Amgen acknowledgement is required for subject 
participation.   
Any changes regarding concomitant medications should be recorded on the subject’s 
source documents and the CRF along with the reason for the change: 
6.2 
Dose Modification 
6.2.1 
Dose-cohort Study Escalation/De-escalation and Stopping Rules 
There are no dose-cohort study escalation/de-escalation or stopping rules for this study. 
6.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.2.1 
Amgen Investigational Product:  Olpasiran 
The reason for withholding dose of olpasiran is to be recorded on each subject’s CRF(s). 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.7 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on preparation, handling, storage, accountability, destruction, 
or return of the investigational product during the study are provided in the IPIM. 
6.4 
Measures to Minimize Bias:  Randomization and Blinding 
6.4.1 
Method of Treatment Assignment 
Subjects will be randomized in 1:1:1:1:1 allocation ratio, to 4 different doses of olpasiran 
and placebo, respectively, in a double-blind manner.  
The randomization will be performed by IRT, and the randomization number will be 
provided by the IRT.  Subjects are considered randomized once a unique subject 
randomization number has been assigned. 


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The randomization will be stratified by: 
 
Screening Lp(a)  200 nmol/L vs.  200 nmol/L, and by 
 
Region (Japan vs. Non-Japan) 
The randomization date is to be documented in the subject’s medical record and on the 
enrollment CRF. 
6.4.2 
Blinding 
This is a double-blind study.  Treatment assignment will be blinded to all subjects, site 
personnel, and Amgen as described below. 
6.4.2.1 
Site Personnel Access to Individual Treatment Assignments 
A subject’s treatment assignment is to only be unblinded by the investigator when 
knowledge of the treatment is essential for the further management of the subject on this 
study or may potentially impact the safety of the subject.  Unblinding at the study site for 
any other reason will be considered a protocol deviation.  It is encouraged that the 
Amgen Trial Manager be notified before the blind is broken unless the investigator 
believes that identification of the study treatment is required for a medical emergency.  If 
this is not possible, the Amgen Trial Manager must be notified within 24 hours after 
breaking the blind.  The date and reason that the blind was broken must be recorded in 
the source documentation. 
6.4.2.2 
Access to Individual Subject Treatment Assignments by Amgen or 
Designees 
The study will be formally unblinded to Amgen or Amgen designees after treatment 
period is ended, database is locked, and the snapshot is taken for end of 
treatment analysis.  Sites and subjects will not have access to unblinded information 
until the study is formally ended at EOS (as defined in Section 4.4.1), database is 
locked, and the snapshot is taken for final analysis.  Unblinding and potentially 
unblinding information is not to be distributed to the study team, investigators or subjects 
prior to the study being formally unblinded except as specified (eg, Section 6.4.2.1).  
Staff from Clinical Supply Chain, Biological Sample Management, Clinical Pharmacology 
Modeling and Simulation (CPMS), Computational Biology, Clinical Immunology, Clinical 
Biomarkers and Diagnostics, Global Statistical Programming and Global Biostatistical 
Sciences departments who may be responsible for tracking, assaying, or analyzing 
biological samples and/or data during the conduct of this study are considered unblinded 
to the treatment assignments in this study.  These individuals will not have access to 
subject level clinical data apart from the sample types they are assaying and/or 


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analyzing during the course of the study and they will not be involved in study conduct 
decisions or communications with the sites or subjects. 
An exposure-response analysis will be performed to support dose selection for a 
phase 3 registrational study.  The exposure-response analysis team, including CPMS, 
Global Statistical Programming, and Global Biostatistical Sciences may be unblinded.  
The analysis plan for the exposure-response analysis will detail the analyses and 
describe the timing for unblinding according to Amgen’s standard operating procedure.   
See Section 8.2.5 for clinical laboratory results that will be blinded from the Amgen study 
team, site staff, and subjects.   
In addition, study team members directly involved with the conduct of the study, 
investigators, and subjects will remain blinded to the results of the interim analyses 
unless specified.  Amgen staff with access to the interim analysis results will be specified 
and documented according to Amgen’s standard operating procedure.  The interim 
analyses results may be used to support company internal discussions and external 
interactions with regulatory agencies.   
6.5 
Treatment Compliance 
Study treatment are to be administered at study visits by authorized investigational site 
study staff.  Each injection will be documented. 
6.6 
Treatment of Overdose 
Overdose with this product has not been reported.  No specific antidote exists.  In the 
case of an overdose, the subject should be treated symptomatically, and supportive 
measures implemented as necessary. 
6.7 
Prior and Concomitant Treatment 
6.7.1 
Prior Treatment 
Prior lipid-altering therapies that were being taken/used from 12 months prior to 
enrollment through the first dose of investigational product will be collected.  Therapy 
name, dose, unit, frequency, start and stop dates will be collected. 
6.7.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.1.6. 


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Any lipid-altering therapy, including statins, that were being taken by the subject at 
screening and enrollment must remain stable throughout the study, including the 
screening, treatment and extended safety follow-up periods.  Lipid-altering therapies are 
not required for study participation.  If any changes to lipid-altering therapies are 
medically warranted after randomization, the Amgen medical monitor or designee should 
be consulted before making the change, if possible. 
Concomitant therapies are to be collected from informed consent through the EOS.  For 
lipid-altering therapies and diabetes therapies (if applicable), collect therapy name, dose, 
unit, frequency, start and stop dates, reason for stop or change. For all other 
concomitant therapies, collect therapy name, start and stop dates. 
7. 
Discontinuation Criteria 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product, device, and/or other protocol-required therapies, protocol procedures, or the 
study as a whole at any time prior to study completion for the reasons listed in 
Sections 7.1, 7.2.1, and 7.2.2. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss with 
the subject the possibilities for continuation of the Schedule of Activities (see Table 1-1) 
including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and must document this decision in the subject’s medical records.  Subjects who have 
discontinued investigational product and/or other protocol-required therapies or 
procedures should not be automatically removed from the study.  Whenever safe and 
feasible, it is imperative that subjects remain on-study to ensure safety surveillance 
and/or collection of outcome data. 


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Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 11.3. 
Reasons for early removal from protocol-required investigational product(s) or 
procedural assessments may include any of the following: 
 
Decision by Sponsor 
 
Lost to follow-up 
 
Death 
 
Adverse event 
 
Subject request 
 
Pregnancy 
7.2 
Discontinuation From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data  
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study, and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must notify Amgen accordingly (see 
Section 11.6 for further details).  Refer to the Schedule of Activities (Table 1-1) for data 
to be collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
7.2.1 
Reasons for Removal From Washout Period, Run-in Period, or 
Invasive Procedures 
Reasons for removal from the washout period, run-in period, invasive procedures are not 
applicable for this study. 
7.2.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
Decision by sponsor 
 
Withdrawal of consent from study 
 
Death 
 
Lost to follow-up 


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7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-1).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 
8.1 
General Study Periods 
8.1.1 
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 register the subject in the IRT and screen the subject in 
order to assess eligibility for participation.  The screening window is up to 28 days 
(4 weeks) and all activities shown in the Schedule of Activities for screening must be 
completed in this time period. 


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For a subject to be eligible for study participation, the subject must have a fasting 
Lp(a)  150 nmol/L confirmed during screening.  This serum sample needs to be 
collected after informed consent is obtained but prior to treatment start (see 
Section 8.2.9).  Diagnoses of coronary artery disease, atherosclerotic cerebrovascular 
disease, or peripheral arterial disease are expected to be consistent with locally 
applicable professional society guidelines. 
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 5.5) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time if they failed criteria other than elevated Lp(a).  
Rescreen subjects must first be registered as screen failures in IRT and subsequently 
registered as rescreens.  Once the subject is registered as rescreened, a new 28-day 
(4 week) screening window will begin.  Subjects will retain the same subject identification 
number assigned at the original screening and must complete all screening 
assessments, except for the retesting of Lp(a).  If the rescreening period begins more 
than 30 days after the original signing of the ICF, all screening procedures, including 
informed consent, must be repeated. 
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-1).  On-study visits may be 
completed within  3 day, aside from Day 2 visit which may be completed  2 day.  The 
date of the first dose of investigational product is defined as day 1 and will occur on day 
of randomization.  All subsequent doses and study visits will be scheduled based on the 
day 1 date, with the final day of the treatment period defined as week 48.  Administration 
of investigational product is to be administered last during each visit that it is required, 
except when post-dose PK samples are being collected.  
Telemedicine, paper PRO completion, and home healthcare visits may be implemented 
at randomization/day 1 onward, where circumstances outside the subject’s, site’s, and 
sponsor’s control (eg, pandemic) result in study visits being unable to be conducted.  
The sponsor must authorize use of these approaches in advance of each visit, and this 
approach may only be used where allowable by local health authorities, ethics 


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committees, and healthcare provider guidelines (eg, hospital policies).  The minimum 
possible number of visits should occur outside the clinic, and visits should return to 
“in-clinic” at the earliest possible opportunity. 
Subjects that withdraw from study treatment should continue with on-study visits (see 
Section 7.1 for more details).  If a subject withdraws from the study early, all efforts 
should be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  The procedures for the EOS visit should be completed at the 
time of withdrawal (Section 8.1.4). 
8.1.3 
Extended Safety Follow-up 
Visits will occur per the Schedule of Activities (Table 1-1).  Extended Safety Follow-up 
visits should be completed within  7 days.  The Extended Safety Follow-up period will 
be conducted for a minimum of 24 weeks in duration from week 48. 
If a subject withdraws from the study early, all efforts should be made to complete and 
report the observations as thoroughly as possible up to the date of withdrawal.  The 
procedures for the EOS visit should be completed at the time of withdrawal 
(Section 8.1.4).   
8.1.4 
End of Study 
The EOS visit will occur after the Extended Safety Follow-up period, or at the time a 
subject discontinues from the study early.   
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects must sign and personally date the IRB/IEC approved informed consent 
before any study-specific procedures are performed. 
8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact on biomarkers variability 
and pharmacokinetics (PK) of the protocol-required therapies.  


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8.2.1.3 
Medical History 
The Investigator or designee will collect a complete medical history that started or was 
ongoing within 6 months prior to enrollment through day 1.  Medical history will include 
information on the subject's concurrent medical conditions.  In addition to the medical 
history above, the following should be collected back to the date of original diagnosis: 
 
cardiovascular history, including details of atherosclerotic cardiovascular disease and 
elevated Lp(a) 
 
history of cancer and/or malignancy 
 
history of immunologic or chronic inflammatory disease 
 
history of hepatobiliary dysfunction (including asymptomatic and/or transient liver 
function test abnormalities) 
 
history of renal disorder or abnormal renal findings 
 
history of non-stroke related neurological findings (eg, peripheral neuropathy) 
 
history of platelet disorder or coagulopathy 
 
diabetes mellitus history including, but not limited to, duration and complications 
(eg, acute metabolic complications, retinopathy, neuropathy) 
 
familial history of diabetes mellitus 
 
familial history of cardiac disorder 
Record all findings on the medical history CRF.  The current severity will be collected for 
each condition that has not resolved. 
8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.4.1 
Neurological and Muscular Examination 
The clinical neurologic musculoskeletal examination will be performed to assess signs of 
new onset peripheral neuropathy or myopathy. The examination should be reported in 
the subject records and must include the following assessments: 
 
muscle mass and tone, presence of tremor, fasciculation or paralysis 
 
strength in all extremities, including proximal and distal muscular groups 
 
gait, by observation of a short regular walk, heel and toe walk 
 
symmetry of sensitivity to pressure (dull tool), temperature and pain (sharp tool) 
 
proprioception in upper and lower extremities 
 
symmetry of reflexes assessed on the upper extremities (biceps, triceps and 
brachioradial) and lower extremities (patellar and achilles) 


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If there is clinical evidence of treatment-emergent neuropathy or myopathy, dosing will 
be suspended, the subject will be directed to a specialist for a complete neurologic or 
musculoskeletal assessment. The identified neurologic or musculoskeletal abnormality is 
to be reported on the adverse Events CRF. 
8.2.1.5 
Physical Measurements 
Height in centimeters should be measured without shoes.  Weight in kilograms should 
be measured without shoes.  
Waist circumference:  Subjects should wear minimal clothing to ensure that the 
measuring tape is correctly positioned.  Subjects should stand erect with the abdomen 
relaxed, arms at the sides, feet together and with their weight equally divided over both 
legs.  To perform the waist measurement, the lowest rib margin is first located and 
marked.  The iliac crest is then palpated in the midaxillary line, and also marked.  It is 
recommended to apply an elastic tape horizontally midway between the lowest rib 
margin and the iliac crest, and tie firmly so that it stays in position around the abdomen 
about the level of the umbilicus.  The elastic tape thus defines the level of the waist 
circumference, which can then be measured by positioning the measuring tape over the 
elastic tape.  Subjects are asked to breathe normally, and to breathe out gently at the 
time of the measurement to prevent them from contracting their muscles or from holding 
their breath.  Measurements should be performed using the same procedure throughout 
the study.  The reading is taken to the nearest centimeter or 1/2 inch and entered in the 
source document. 
8.2.2 
Efficacy Assessments 
Planned time points for all efficacy assessments are listed in the Schedule of Activities 
see (Table 1-1).  Serum Lp(a), LDL-C, and ApoB will be collected with other clinical 
laboratory assessments described in Section 8.2.5. 
8.2.3 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 1-1). 
8.2.3.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic blood pressure and 
heart rate.  Subject must be in a supine position in a rested and calm state for at least 
5 minutes before blood pressure assessments are conducted.  If the subject is unable to 
be in the supine position, the subject should be in most recumbent position as possible.  


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The position selected for a subject should be the same that is used throughout the study 
and documented on the vital sign CRF.  Record all measurements on the vital signs 
CRF. 
8.2.3.2 
Survival Status  
Survival status should be obtained for all subjects within the limits of local law.  
This includes subjects who withdraws consent, or subjects considered lost to 
follow-up, or subjects unwilling to continue schedule of assessments and should 
include interrogation of medical, national, and public databases, if necessary.  If 
deceased, the date and reported cause of death should be obtained. 
8.2.3.3 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The principal 
investigator 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.  Findings should 
be recorded on the ECG eCRF. 
8.2.4 
Adverse Events and Serious Adverse Events  
8.2.4.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.4.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the Amgen Standard 
Grading Scale and is described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment through the EOS are 
reported using the Events CRF. 
8.2.4.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through EOS are reported using the Events CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s knowledge of the event, as indicated in 


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Section 11.4.  The investigator will submit any updated serious adverse event data to the 
sponsor within 24 hours of it being available. 
8.2.4.1.3 
Serious Adverse Events After the Protocol-required Reporting 
Period 
After EOS, there is no requirement to actively monitor study subjects with regards to 
study subjects treated by the investigator.  However, if the investigator becomes 
aware of serious adverse events suspected to be related to investigational product, 
then these serious adverse events will be reported to Amgen within 24 hours following 
the investigator’s awareness of the event using the Serious Adverse Event 
Contingency Form. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study.  
8.2.4.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.2.4.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required to 
proactively follow each subject at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.3).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following knowledge of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 


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8.2.4.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements.   
To comply with worldwide reporting regulations for serious adverse events, the treatment 
assignment of subjects who develop serious, unexpected, and related adverse events 
may be unblinded by Amgen before submission to regulatory authorities.  Aggregate 
analyses may also be unblinded by the Safety Assessment Team, as appropriate.  
Investigators will receive notification of related serious adverse events reports sent to 
regulatory authorities in accordance with local requirements. 
8.2.4.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.4.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and pregnancy details for 
female partners of male subjects will be collected after the start of study treatment and 
until 90 days after receiving the last dose of study drug. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 


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Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, and ectopic pregnancy) are considered serious adverse events. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.5 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-1) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Events CRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the laboratory manual and the Schedule of Activities 
(Table 1-1).  
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been formally unblinded.  
In order to protect the blinding of the double-blind treatment period, the following labs will 
be blinded to the Amgen study team and site staff after day 1 until the study has been 
formally unblinded, and will not be reported to sites:   
 
Serum Lp(a) 
 
Lipid panel (see Appendix 2 Section 11.2 for a list of analytes)  
 
high sensitivity C-reactive protein (hs-CRP) 
 
high sensitivity Interleukin 6 (hs-IL-6) 
 
anti-olpasiran antibodies 
 
ApoA1 
 
ApoB 


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In addition, investigators and staff involved with this trial and all medical staff involved in 
the subject’s medical care should not perform non-protocol testing of these analytes 
during a subject’s study participation and until the end of the study, to prevent unblinding 
the patient and site to the treatment assignment, except when it is medically necessary.  
If a local lipid panel is drawn, all reasonable steps must be undertaken to avoid informing 
the subject and study personnel of the results.   
If triglycerides are  1000 mg/dL (11.3 mmol/L) at any scheduled assessment, the 
investigator will be informed, and a fasting triglyceride repeat test will be requested.  If 
the retest confirms triglycerides  1000 mg/dL (11.3 mmol/L), the Amgen medical 
monitor and the investigator will be informed so that appropriate medical follow up for the 
subject can be initiated. 
Pregnancy Testing 
A highly sensitive (serum) pregnancy test should be completed at screening and a 
screening urine pregnancy test should be completed the day of initiation of 
investigational product (prior to dosing) for females of childbearing potential.   
Note:  Females who have undergone a bilateral tubal ligation/occlusion should have 
pregnancy testing per protocol requirements.  (If a female subject, or the partner of a 
male subject, becomes pregnant it must be reported on the Pregnancy Notification 
Form, see Figure 11-2).  Refer to Section 11.5 for contraceptive requirements.  
Additional urine pregnancy testing should be performed prior to each administration of 
protocol-required therapies and 90 days after the last dose of investigational product.  In 
the case of a positive urine result, a serum pregnancy test should be performed for 
confirmation. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.2.6 
Pharmacokinetic Assessments 
All subjects enrolled will have PK samples assessed. 
Blood samples will be collected for measurement of serum concentrations of olpasiran 
as specified in the Schedule of Activities (Table 1-1 and Table 1-2).  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. 


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Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
8.2.6.1 
Pharmacokinetic Sub-study 
A PK sub-study will be conducted with a total of approximately 75 subjects 
(approximately 15 from each treatment cohort).  A maximum of 3 samples may be 
collected at additional time points during the study if warranted and agreed upon 
between the investigator and the sponsor.  Pharmacokinetic samples will be collected as 
per the PK sub-study schedule of assessments (see Table 1-1 and Table 1-2). 
8.2.7 
Pharmacogenetic Assessments 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of cardiovascular diseases 
and/or to identify subjects who may have positive or negative response to olpasiran.  No 
additional samples are collected for this part of the study.  For subjects who consent to 
this/these analysis/analyses, DNA may be extracted from residual cell pellets retained 
from selected biomarker plasma blood draws. 
The final disposition of samples will be described in Section 11.6.  
8.2.8 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected according to the time points 
specified in the Schedule of Activities (Table 1-1).  Bioanalytical testing for anti-olpasiran 
antibodies will be conducted on these samples only if there are unexpected 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-drug 
antibodies during the study. 
Subjects who test positive for binding antibodies at the final antibody-scheduled time 
point 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.   


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8.2.9 
Biomarkers  
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention. 
8.2.9.1 
Biomarker Assessment to Determine Eligibility 
Blood Samples 
For a subject to be eligible for study participation, a subject must have a Lp(a) value of 
 150 nmol/L demonstrated during screening.  Blood sample(s) need(s) to be collected 
after informed consent is obtained but prior to randomization.  Screening for Lp(a) will be 
conducted using either an approved or investigational assay, investigational devices will 
follow regional regulatory requirements.  The Lp(a) assay will be developed by Roche 
and screening will take place at a central laboratory as described in the Schedule of 
Activities (Table 1-1) and Appendix 2 (Section 11.2). 
8.2.9.2 
Biomarker Assessment During the Study 
Serum samples are to be collected for assessment of hs-CRP and hs-IL-6 at the time 
points specified in the Schedule of Activities (Table 1-1); however, the results of these 
biomarkers will not be included in the final clinical study report unless noteworthy. 
Biomarker Discovery 
Samples will also be collected for biomarker analysis, eg, to evaluate potential 
biomarkers that may correlate with treatment response.   
Blood will be collected for biomarker discovery at the time points specified in the 
Schedule of Activities (Table 1-1), but results will not be reported in the final clinical 
study report.   
Biomarker samples may include:  oxidized phospholipids on apolipoprotein B-100 
(OxPL/ApoB) and Lp(a) isoform size.  
8.2.9.2.1 
Biomarker Development/Future Research 
Biomarker Development refers to using samples collected for Biomarker Discovery for 
future research after the study ends. 
Biomarker development can be useful in developing markers to identify disease 
subtypes, guide therapy, and/or predict disease severity.   


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If consent is provided by subjects, biomarker development samples collected at the time 
points specified in the Schedule of Activities (Table 1-1) will be retained for future 
biomarker development as described in Appendix 6 (Section 11.6). 
Amgen or another third-party manufacturer may attempt to develop test(s) designed to 
identify subjects most likely to respond positively or negatively to olpasiran to investigate 
and further understand cardiovascular diseases. 
8.2.10 
Optional Sub-studies 
See Section 8.2.6.1 for the PK sub-study details. 
Obtain confirmation that the optional PK sub-study ICF has been signed prior to 
performing optional PK sub-study procedures. 
8.2.11 
Other Assessments  
8.2.11.1 
PROMIS Global Health 
The PROMIS Global Health is a 10-item static measure of global ratings of the five 
primary PROMIS domains (physical function, fatigue, pain, emotional distress, and 
social health) and general health perceptions that cut across domains. The first seven 
items do not use a specific recall period, and the last three items have a recall period of 
“the past seven days”.  The first nine items of the PROMIS Global Health use a five-point 
Likert-type scale. Response options for the first six items (Global 01 to 05 and Global 09) 
range from “Excellent”, corresponding to a score of 5 to “Poor”, corresponding to a score 
of 1; response options for item 7 (Global 06) ranged from “Completely”, corresponding to 
a score of 5 to “Not at all”, corresponding to a score of 1; response options for item 8 
(Global 10) ranged from “Never”, corresponding to a score of 5 to “Always”, 
corresponding to a score of 1; and response options for item 9 (Global 08) ranged from 
“None”, corresponding to a score of 5 to “Very severe”, corresponding to a score of 1. 
Item 10 (Global 07) uses an 11-point numeric rating scale with 0 corresponding to “No 
pain” and 10 corresponding to “Worst pain imaginable”.  The PROMIS Global Health 
should be completed first at study visits and takes approximately 3 minutes to complete 
using the provided ePRO tablet device. 
8.2.11.2 
Exit Survey 
Subjects will be asked to complete an Exit Survey at week 48 to provide feedback on 
their experience in the study and to help inform future studies.  The Exit Survey will take 
approximately 10 minutes to complete using the provided ePRO tablet device. 


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
The null hypothesis is that there is no difference between olpasiran and placebo in 
percent change from baseline in Lp(a) at week 36 in subjects with atherosclerotic 
cardiovascular disease and with elevated Lp(a). 
9.2 
Sample Size Determination 
Assuming standard deviation of 30 as observed in phase 1 study, a 5 drop-out rate 
and with Bonferroni multiplicity adjustment to control family-wise type 1 error rate at 
0.05, at least 48 subjects per arm provides at least 90 power to detect a treatment 
difference of 25 between active and placebo arm in mean percent change of Lp(a) 
from baseline.  It is expected to have 99 power to detect a treatment effect of -80 vs. 
-3 between active and placebo arms in mean percent change of Lp(a) from baseline.  
Considering 5 drop-out rate, at least 48 subjects per arm (at least 192 subjects in the 4 
active treatment arms) provides a 95 confidence of detecting 1 case of an adverse 
event at an incidence of 1/60.  
Up to a total of approximately 290 subjects may be enrolled to accommodate individual 
country-specific enrollment requirements. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
Full Analysis Sets (FAS):  FAS includes all randomized subjects who received at least 
one dose of investigational product and will be used to perform the efficacy analysis 
based on randomized treatment group.  
For safety analysis, FAS will be used based on the actual treatment received. 
9.3.2 
Covariates 
Baseline covariates include, but are not limited to: 
 
Stratification factors 
 
Screening Lp(a) ( 200 nmol/L vs.  200 nmol/L) 
 
Region (Japan vs. Non-Japan) 
 
Age 
 
Sex 
 
Race 
 
Baseline Lp(a) 


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9.3.3 
Subgroups 
Subgroups include, but are not limited to the following: 
 
Stratification factors 
 
Screening Lp(a) ( 200 nmol/L vs.  200 nmol/L) 
 
Region (Japan vs. Non-Japan) 
 
Age ( 65 years,  65 years) 
 
Sex (male, female) 
 
Race (black, white, other) 
 
Baseline Lp(a) 
 
Lipid lowering therapy at baseline (high intensity, not high intensity) 
9.3.4 
Handling of Missing and Incomplete Data 
All attempts will be made to capture missing or partial data for this trial prior to the data 
lock.  The frequency and pattern of missing data for efficacy endpoints will be assessed 
through descriptive summaries of the measurements over time. 
Details on the imputation rules for partial dates relating to adverse events, concomitant 
medications and historical events are provided in the Statistical Analysis Plan (SAP) 
9.4 
Statistical Analyses 
The first version of the SAP will be developed and finalized before the snapshot of the 
primary analysis.  Below is a summary of the timing and methods for the planned 
statistical analyses.  The final analysis will be conducted and reported following the 
EOS, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Administrative Interim Analyses for Efficacy 
An interim analysis will be performed when approximately 240 subjects have had the 
opportunity to complete week 24 assessments or have early terminated.  At that point, 
approximately 120 subjects may have had the opportunity to complete week 36 
assessments or have early terminated.  The study continues regardless of the 
administrative interim results. 
Interim analysis results will be reviewed by an Interim Analysis Review Steering 
Committee (IARSC) which consists of internal experts, who are independent of the study 
team.  Further detail regarding the interim analysis process in protecting trial integrity will 
be provided by an IARSC Charter. 


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9.4.1.2 
Primary Analysis 
Primary analysis will be performed when all randomized subjects have had the 
opportunity to complete the week 36 assessments or have early terminated.  At that 
time, the database related to the primary analyses will be cleaned, processed and a 
snapshot will be taken. 
Only the unblinded team will be unblinded at the primary analysis.  Individuals unblinded 
are prohibited from remaining involved in the conduct of the study. 
9.4.1.3 
End of Treatment Period Analysis 
The end of treatment period analysis will be performed when all randomized subjects 
have had the opportunity to complete week 48 assessments or have early terminated.  
At that time, the database related to the end of treatment analyses will be cleaned, 
processed and a snapshot will be taken.   
The study will be formally unblinded to Amgen or Amgen designees after 
treatment period is ended, database is locked, and the snapshot is taken for end 
of treatment analysis.  Sites and subjects will not have access to unblinded 
information until the study is formally ended at EOS (as defined in Section 4.4.1), 
database is locked, and the snapshot is taken for final analysis.   
9.4.1.4 
Final Analysis 
Final analysis will be performed when all randomized subjects either complete the 
extended safety follow-up and ended the study or early terminate from the study.  At that 
time, the database related to the final analysis will be cleaned, processed and the 
database will be locked.  All efficacy and safety analyses during the extended follow-up 
period will be performed. 
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Unless specified otherwise, efficacy analyses will be performed on the FAS by 
randomized treatment group, and safety analyses will be performed on the FAS by 
actual treatment group. 
All categorical variables will be summarized using the number and percent of subjects 
and all continuous variables will be summarized using mean, standard error or standard 
deviation, median, minimum, maximum, and number of subjects with observations. 
Analysis of exploratory endpoints will be specified in SAP. 
Definition of Baseline Lp(a): 


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Baseline Lp(a) is defined as the mean of the two most recent non-missing Lp(a) values 
measured through central lab prior to or on study day 1.  If for any reason only 1 value is 
available, then that value will be used as baseline. 
9.4.2.2 
Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
The analysis of percent change from baseline in Lp(a) at week 36 will be 
performed when all randomized subjects have had the opportunity to 
complete the week 36 assessments or have early terminated.  A repeated 
measures linear effects model including terms for treatment group, 
stratification factors, scheduled visit and the interaction of treatment with 
scheduled visit will be used.  The least squares means (LS means) by 
treatment group and the treatment difference (olpasiran - placebo) based on 
the model above will be summarized.  The Hochberg procedure will be used 
to control the type I error for multiple comparisons between active and 
placebo arms. 
A sensitivity analysis will be performed using multiple imputation to impute 
missing data.  Details of the imputation rules for the sensitivity analysis will be 
provided in the SAP. 
Additional analysis of the primary endpoint will be explored using Multiple 
Comparison Procedure - Modelling (MCP-Mod) methodology  
(Bretz et al, 2005).  Details will be provided in the SAP. 
Secondary 
Analysis of the secondary endpoints will be performed when all randomized 
subjects have had opportunity to complete week 48 assessments or have 
early terminated. 
Analysis of the secondary endpoints (including percent change from baseline 
at week 36 in ApoB and LDL-C, and percent change from baseline at 
week 48 in ApoB, Lp(a) and LDL-C) will be performed similarly to the analysis 
of the primary endpoint. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class, high level term, and preferred term.  Tables of fatal adverse events, serious 
adverse events, adverse events leading to withdrawal from investigational product, and 
significant treatment emergent adverse events will also be provided.   
9.4.2.3.2 
Laboratory Test Results 
The analyses of safety laboratory endpoints will include summary statistics at each 
scheduled visit by treatment group. Shifts in grades of select safety laboratory values 
between baseline and the maximum post-baseline grade will be tabulated by treatment 
group. 


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9.4.2.3.3 
Vital Signs 
The analyses of vital signs will include summary statistics at each scheduled visit by 
treatment group. 
9.4.2.3.4 
Electrocardiogram 
The ECG measurements from this clinical study are performed as per standard of care 
for routine safety monitoring, rather than for purposes of assessment of potential 
corrected QT (QTc) effect.  Since these evaluations may not necessarily be performed 
under the rigorous conditions expected to lead to meaningful evaluation of QTc data; 
summaries and statistical analyses of ECG measurements are not planned, and these 
data would not be expected to be useful for meta-analysis with data from other trials. 
9.4.2.3.5 
Antibody Formation 
Identified anti-olpasiran binding antibodies will be summarized descriptively.  Subject 
level listing may be provided instead of summary if there is a small number of subjects 
that are tested for anti-olpasiran antibodies. 
9.4.2.3.6 
Exposure to Investigational Product 
The exposure to IP will be summarized using descriptive statistics by treatment group. 
9.4.2.3.7 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term or category for each treatment group as coded by the World Health 
Organization Drug dictionary. 


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11. 
Appendices 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
Abbreviation or Term 
Definition/Explanation 
A1C 
glycated hemoglobin 
ACC/AHA 
American College of Cardiology/American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ApoB 
apolipoprotein(B) 
ASGPR 
asialoglycoprotein receptor 
ASO 
Antisense oligonucleotides 
AST 
aspartate aminotransferase 
AUC 
area under the concentration time curve 
Baseline Lp(a) 
mean of the two most recent non-missing Lp(a) values 
measured through central lab prior to or on study day 1.  If for 
any reason only 1 value is available, then that value will be used 
as baseline. 
CABG 
coronary artery bypass grafting 
CFR 
U.S. Code of Federal Regulations 
Cmax 
maximum observed concentration 
COVID 19 
Coronavirus disease-19 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CRF 
case report form 
DILI 
drug induced liver injury 
DRT 
Data Review Team 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
Enrollment 
defined as the day a subject has signed the ICF 
EOS 
end of study 
Exposure-Response  
Analysis 
mechanism-based modeling & simulation and statistical 
analyses based on individual pharmacokinetic (PK) exposure 
(eg, population pharmacokinetic modeling) and response, which 
may include biomarkers, pharmacodynamic (PD) effects, 
efficacy and safety endpoints. 
End of Follow-up 
defined as when the last subject completes the last 
protocol-specified assessment in the study   
End of Study for Individual 
Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 


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Abbreviation or Term 
Definition/Explanation 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or 
receives an intervention for the final collection of data for the 
primary endpoint(s), for the purposes of conducting the primary 
analysis, whether the study concluded as planned in the protocol 
or was terminated early  
End of Study (end of trial) 
defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit), following any additional parts in the 
study (eg, long-term follow-up), as applicable 
End of Treatment 
defined as the last assessment for the protocol-specified 
treatment phase of the study for an individual subject 
ESC/EAS 
European Society of Cardiology/European Atherosclerosis 
Society 
ESFU 
extended safety follow-up 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
GalNAc 
N-Acetylgalactosamine 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HRT 
hormone replacement therapy 
hs-CRP 
high sensitivity C-reactive protein 
hs-IL-6 
high sensitivity Interleukin 6 
IARSC 
Interim Analysis Review Steering Committee 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IND 
Investigational new drug 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IRT 
interactive response technology that is linked to a central 
computer in real time as an interface to collect and process 
information 
LDL-C 
low-density lipoprotein cholesterol 
LS means 
least square means 
Lp(a) 
lipoprotein(a) 
NCT 
National Clinical Trials 


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Abbreviation or Term 
Definition/Explanation 
NYHA 
New York Heart Association 
OCEAN(a) 
Olpasiran trials of Cardiovascular Events And LipoproteiN(a) 
reduction 
OxPL/ApoB 
oxidized phospholipids on apolipoprotein B-100 
PCI 
percutaneous coronary intervention 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QoL 
quality of life 
QTc 
Corrected QT 
Q12W 
once every 12 weeks 
Q24W 
once every 24 weeks 
Randomization 
defined as the day a subject has met all eligibility criteria and is 
assigned a treatment arm 
RISC 
RNA-induced silencing complex 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
siRNA 
small interfering ribonucleic acid 
Study Day 1 
defined as the first day that protocol-specified investigational 
product(s)/protocol-required therapies is/are administered to the 
subject 
Source Data 
information from an original record or certified copy of the 
original record containing patient information for use in clinical 
research.  The information may include, but is not limited to, 
clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents (original records 
or certified copies).  (ICH Guideline [E6]).  Examples of source 
data include Subject identification, Randomization identification, 
and Stratification Value. 
TBL 
total bilirubin 
ULN 
upper limit of normal 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the central laboratory, except for 
urine pregnancy for females of childbearing potential which will be done by the study 
staff or local laboratory.  
Local laboratory results are only required in the event that additional tests are needed for 
monitoring of a possible drug induced liver injury (DILI) event per Section 11.7.   
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Sections 5.1 to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 11-1.  Analyte Listing 
Chemistrya 
Hematology 
Urinalysis 
ALT (SGPT) 
Albumin 
ALP 
Amylase 
Anion Gap 
AST (SGOT) 
Bicarbonate, 
Total CO2  
Bilirubin, Direct, 
Conjugated 
Bilirubin, Indirect 
Bilirubin, Total 
Calcium 
Chloride 
CK 
Creatinine 
eGFR 
FSH 
GGT 
Glucose 
(fasting)  
hs-CRP  
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
BUN or Urea 
Nitrogen 
Uric acid 
Adjusted 
calcium 
LDH 
 
Absolute Neutrophil 
Count 
Agranular Cells 
Hematocrit 
Hemoglobin 
Hypersegmented 
Neutrophil 
Hyposegmented 
Neutrophil 
MCH 
MCHC 
MCV  
Platelets count 
RBC count 
RBC morphology 
RDW 
WBC count 
WBC Differential 
 Bands/stabs 
 Eosinophils 
 Basophils 
 Lymphocytes 
 Total neutrophils 
 Monocytes 
 Segmented 
neutrophils 
Macro: 
Appearance 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte 
Esterase 
pH 
Protein 
Specific gravity 
Urine Color 
Urobilinogen 
 
Micro: 
Bacteria 
Epithelial cells 
Casts 
Crystals 
RBCs 
WBCs 
 
Page 1 of 2 


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Table 11-1.  Analyte Listing  
Lipid Panel 
Coagulation 
Other Labs 
Biomarker 
Assessment 
Local 
Laboratory 
Total Cholesterol 
HDL-C 
LDL-C  
Lp(a) 
Non-HDL-C 
Total 
cholesterol/HDL-C 
ratio 
Triglycerides 
VLDL-C 
PT/INR 
APTT 
Fibrinogen 
Fibrin split 
products 
D-dimer   
Apolipoprotein A1 
Apolipoprotein B 
ApoB/ApoA1 ratio 
Olpasiran Antibodies 
Hemoglobin A1C 
Serum Pregnancy 
Pharmacokinetics 
hs-CRP 
hs-IL-6 
OxPL/ApoB 
Lp(a) isoforms 
Urine 
Pregnancy 
(completed by 
study staff or 
local 
laboratory) 
Lactate (if 
applicable)b 
 
Additional 
observational 
labs for DILI 
criteria (if 
applicable) 
Page 2 of 2 
a Fasting is only required when fasting glucose sample is taken.  When fasting is required, subject must be 
fasting (not eating or drinking anything except for water) for at least 9 hours. 
b To be performed at the discretion of the investigator or designee if anion-gap metabolic acidosis is 
identified.   
ALP  alkaline phosphatase; ALT  alanine aminotransferase; APTT  activated partial thromboplastin time 
AST  aspartate aminotransferase; BUN  blood urea nitrogen; CK  creatine kinase; 
DILI  drug induced liver injury; eGFR  estimated glomerular filtration rate; 
FSH  follicle-stimulating hormone; GGT  gamma glutamyl transferase; HDL  high density lipoprotein; 
HLA  human leukocyte antigen; hs-CRP  high sensitivity C-reactive protein; 
hs-IL-6  high sensitivity Interleukin-6; INR  international normalized ratio; LDH  lactate dehydrogenase; 
LDL  low-density lipoprotein; Lp(a)  lipoprotein(a); MCH  mean corpuscular hemoglobin; 
MCHC  mean corpuscular hemoglobin concentration; MCV  mean corpuscular volume; 
OxPL/ApoB  oxidized phospholipids on apolipoprotein B-100; PT  prothrombin time; 
RBC  red blood cell count; SGOT  serum glutamic-oxaloacetic transaminase; SGPT  serum 
glutamic-pyruvic transaminase; VLDL  very-low-density lipoprotein; WBC  white blood cell count 
Laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded (see 
Section 8.2.5 for details).  


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11.3 
Appendix 3.  Study Governance Considerations 
Clinical Events, Interim Analysis Review Steering, and Data Review Team 
Committee(s) 
Clinical Events Committee 
Deaths and major cardiovascular events will be adjudicated by an independent external 
Clinical Events Committee, using standardized definitions.  Adjudication will include, but 
may not be limited, to the following events: 
 
death by any cause 
 
cardiovascular death 
 
myocardial infarction 
 
hospitalization for unstable angina 
 
coronary revascularization 
 
stroke 
 
transient ischemic attack 
 
cerebrovascular revascularization 
In addition, major adverse limb events (acute limb ischemia, major amputation, or urgent 
peripheral revascularization for ischemia) may also be adjudicated. 
Interim Analysis Review Steering Committee 
Amgen will use an Interim Analysis Review Steering Committee (IARSC) to review 
accumulating efficacy data from the planned administrative interim analyses of Study 
20180109 to support dose selection for a phase 3 registrational study and trigger early 
planning for the phase 3 program, but will not assess for futility.  The IARSC will be an 
internal group within Amgen, but external to the relevant study team for olpasiran.  The 
IARSC will follow guidelines outlined in the IARSC charter.  The charter will set forth the 
governance and responsibilities of the IARSC for olpasiran Study 20180109. 
It is important to note that the IARSC is separate from the Data Review Team (DRT), 
described below.  While both are internal Amgen committees, the IARSC will review 
accumulating efficacy data and the DRT will review accumulating safety data.   
Data Review Team 
In addition to routine pharmacovigilance monitoring by Amgen, an internal unblinded 
DRT will be implemented.  In order to maintain trial integrity, the unblinded data 
reviewed by the DRT will be restricted and not accessible by the olpasiran team.   


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The DRT is a group internal to Amgen, but external to the olpasiran product team with at 
least 3 members, including at least 2 with clinical expertise (eg, a member from Clinical 
or Early Development and a member from Global Patient Safety) and a member from 
Global Biostatistical Science.  The DRT will periodically review accumulating data from 
the ongoing clinical study to enable prompt identification of serious and unexpected 
suspected adverse reactions to ensure no avoidable increased risk for harm to subjects.  
The DRT will follow the procedures outlined in a charter that will detail the DRT 
responsibilities and ensure controls are in place to prevent any unintentional unblinding 
of the olpasiran team involved in conduct of the study.  Serious adverse events, adverse 
events of interest, and relevant clinical laboratory test results, will be reviewed as well as 
any other available important safety information, as deemed necessary.  The DRT will 
perform unblinded comparisons of event rates in investigational and control groups to 
detect serious and unexpected suspected adverse reactions as well as any other safety 
findings that may prompt further actions such as update to the protocol, Investigators’ 
Brochure or Informed Consent Form (ICF).  An ad-hoc DRT may be convened at any 
time for reasons such as a significant and unanticipated safety finding.  In accordance 
with Food and Drug Administration (FDA) guidance on the safety assessment for 
Investigational new drug (IND) safety reporting (FDA, 2015), identification of any serious 
and unexpected suspected adverse reactions will trigger regulatory safety reporting. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
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 Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (eg, subject recruitment advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC).  A copy of the written approval of the 
protocol and informed consent form must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product. 


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Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events occurring at the site, deviations from 
the protocol or other adverse event reports received from Amgen, in accordance with 
local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Informed Consent Process 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the sample 
informed consent form are to be communicated formally in writing from the Amgen Trial 
Manager to the investigator.  The written informed consent form is to be prepared in the 
language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, 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 will then be 
required to sign a statement of informed consent that meets the requirements of  
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the 
informed consent form. 


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The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study unless it is a local requirement.  The 
investigator shall then inform the primary care physician.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record. 
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  Subject withdrawal of consent or discontinuation from 
study treatment and/or procedures must also be documented in the subject’s medical 
records; refer to Section 7. 
Subjects must be re-consented to the most current version of the informed consent 
form(s) during their participation in the study.  
The original signed informed consent form is to be retained in accordance with 
institutional policy, and a copy of the informed consent form(s) must be provided to the 
subject.  
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.  (Refer to ICH GCP guideline, Section 4.8.9.) 
A subject who is rescreened is not required to sign another informed consent form if the 
rescreening occurs within 30 days from the previous informed consent form signature 
date. 
The informed consent form (ICF) will contain a separate section that addresses the use 
of remaining mandatory samples for optional future research.  The investigator or 
authorized designee will explain to each subject the objectives of the future research.  
Subjects will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period.  A separate 


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signature will be required to document a subject’s agreement to allow any remaining 
specimens to be used for future research.  Subjects who decline to participate will not 
provide this separate signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 
Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For serious adverse events reported to Amgen, subjects are to be identified by their 
unique subject identification number, initials (for faxed reports, in accordance with local 
laws and regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are to 
be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 


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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  
Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above. Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.   Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
 
 


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Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC 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.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 


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Case report forms (CRF) must be completed in English.  TRADENAMES (if used) for 
concomitant medications may be entered in the local language.  Consult the 
country-specific language requirements. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the 
Interactive Response Technology system (if used, such as subject ID and randomization 
number) and CRF entries if the CRF is the site of the original recording (ie, there is no 
other written or electronic record of data, such as paper questionnaires for a clinical 
outcome assessment). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 


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 
Investigational product-related correspondence including [Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  
Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 


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11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of Adverse Event 
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. 
 
Note:  Treatment-emergent adverse events will be defined in the Statistical 
Analysis Plan (SAP). 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, 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  
(ie, 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 an 
adverse event/serious adverse event unless it is an intentional overdose taken with 
possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an adverse event or serious adverse event.  Such instances will be 
captured in the efficacy assessments.  However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as adverse event or 
serious adverse event if they fulfill the definition of an adverse event or serious 
adverse event.  
 
Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
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. 
 


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Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 
Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 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. 
 


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Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all Non-Amgen medical devices provided for use in the study (see 
Section 6.1.2 for the list of Non-Amgen medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include, but are not limited to, 
adverse events resulting from insufficient or inadequate instructions for use, adverse 
events resulting from any malfunction of the device, or adverse events resulting from 
use error or from intentional misuse of the device. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility of 
the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 
 
The investigator will then record all relevant adverse event/serious adverse event 
information in the Event case report form (CRF). 
 
The investigator must assign the following adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product, other 
protocol-required therapies; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to investigational product (olpasiran/placebo) 
and/or other protocol-required therapies;  
o Action taken, and 
o Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Events CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to Amgen in lieu of completion of the Events CRF 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 Amgen. 


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 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Amgen Standard Grading Scale as show below: 
Grade 
Definition 
MILD 
Aware of sign or symptom, but easily tolerated 
MODERATE 
Discomfort enough to cause interference with usual activity 
SEVEREa 
Incapacitating with inability to work or do usual activity 
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 adverse event, NOT when it is rated as severe. 
 


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Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product, and/or study-mandated procedure and each occurrence of each adverse 
event/serious adverse event. 
 
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 adverse event/serious adverse event, the investigator must document in 
the medical notes that he/she has reviewed the adverse event/serious adverse 
event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious 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 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Events 
CRF. 
 
The investigator will submit any updated serious adverse event data to Amgen 
within 24 hours of receipt of the information. 
 
 
 


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Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using an electronic Serious Adverse Event Contingency 
Report Form (also referred to as the electronic Serious Adverse Event (eSAE) 
Contingency Report Form) (see Figure 11-1) within 24 hours of the investigator’s 
knowledge of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC has been taken off-line, then the site can report this information on the paper 
based Serious Adverse Event Contingency Report Form (see Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related 
to investigational product will be reported to Amgen if the investigator 
becomes aware of a serious adverse event.  The investigator should use the 
paper-based Serious Adverse Event Contingency Report Form to report the 
event. 


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Figure 11-1.  Sample Electronic Serious Adverse Event Contingency Form 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for female of childbearing potential are 
outlined in Section 5.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
90 days after the last dose of protocol-required therapies. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:   
1) review of subject’s medical records; 2) subject’s medical examination; or  
3) subject’s medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Contraception Methods for Female Subjects of Childbearing Potential 
Highly Effective Contraceptive Methods 
Note: Failure rate of  1 per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 


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 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 
 
Lactational amenorrhea method 
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 through 90 days. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
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 of 
the study drug.  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 an adverse event or serious adverse 
event, any pregnancy complication or report of a congenital anomaly or 
developmental delay, fetal death, or suspected adverse reactions in the neonate will 
be reported as an adverse event or serious adverse event.  Note that an elective 
termination with no information on a fetal congenital malformation or maternal 


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complication is generally not considered an adverse event, but still must be reported 
to Amgen as a pregnancy exposure case. 
 
If the outcome of the pregnancy meets a criterion for immediate classification as a 
serious adverse event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a serious adverse event. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study 
subjects, he or she may learn of a serious adverse event through spontaneous 
reporting.  
 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
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 discontinuing protocol-required therapies, the information will be 
recorded on the Pregnancy Notification Form.  The form (see Figure 11-2) must be 
submitted to Amgen Global Patient Safety within 24 hours of the site’s awareness of 
the pregnancy.  (Note: Sites are not required to provide any information on the 
Pregnancy Notification Form that violates the country or regions local privacy laws). 
 
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. 
 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 219. 


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 
With the female subjects signed authorization for release of mother and infant 
health information, the investigator will collect mother and infant health information 
and complete the lactation questionnaire on any female subject who breastfeeds 
while taking protocol-required therapies through 90 days after discontinuing 
protocol-required therapies. 
Figure 11-2.  Pregnancy and Lactation Notification Forms 
 


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11.6 
Appendix 6.  Sample Storage and Destruction 
Any blood (eg, biomarker, pharmacokinetics [PK]) sample collected according to the 
Schedule of Activities (Table 1-1 and Table 1-2) can be analyzed for any of the tests 
outlined in the protocol and for any tests necessary to minimize risks to study subjects.  
This includes testing to ensure analytical methods produce reliable and valid data 
throughout the course of the study.  This can also include, but is not limited to, 
investigation of unexpected results, incurred sample reanalysis, and analyses for 
method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.  
If informed consent is provided by the subject, Amgen can do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
cardiovascular disease, the dose response and/or prediction of response to olpasiran, 
characterize antibody response, and characterize aspects of the molecule  
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic, biomarker development or other 
exploratory studies are not placed in the subject’s medical record and are not to be 
made available to the subject, members of the family, the personal physician, or other 
third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 


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request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  See 
Section 11.3 for subject confidentiality. 


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11.7 
Appendix 7.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen investigational product or other protocol-required therapies, as specified in the 
Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, 
July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR, and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 


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If investigational product(s) is/are withheld, the subject is to be followed for possible drug 
induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
 3x ULN  
at any time 
 2x ULN 
 
 
OR 
INR 
-- 
 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
 8x ULN at any time 
 5x ULN but  8x ULN for  2 weeks 
 5x ULN but  8x ULN and unable to 
adhere to enhanced monitoring schedule 
 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 3x ULN (when baseline was  ULN) 
 
OR 
ALP 
 8x ULN at any time 
-- 
ALP  alkaline phosphatase; ALT  alanine aminotransferase; AST  aspartate aminotransferase; 
INR  international normalized ratio; TBL  total bilirubin; ULN  upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then olpasiran is to be permanently 
discontinued.  Subjects who clearly meet the criteria for permanent discontinuation (as 
described in Table 11-2) are never to be rechallenged. 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 


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To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate Case Report Form (CRF) (eg, Events CRF) that captures 
information necessary to facilitate the evaluation of treatment-emergent liver 
abnormalities is to be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in  
Table 11-2 or who experience AST or ALT elevations  3 x upper limit of normal (ULN) 
or 2-fold increases above baseline values for subjects with elevated values before drug 
are to undergo a period of “close observation” until abnormalities return to normal or to 
the subject’s baseline levels.  Local laboratory results are required in the event that 
additional tests are needed for DILI criteria.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL  2x ULN or INR  1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin (Ig)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 


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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 
 
Appropriate blood sampling for pharmacokinetic 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 considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  


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Page 1 of 15 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 3 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled Phase 2 Study to 
Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) (a GalNAc conjugated 
Small Interfering RNA [siRNA]) in Subjects With Elevated Lipoprotein(a) 
 
Amgen Protocol Number Olpasiran (AMG 890) 20180109 
EudraCT number:  2019-003688-23 
NCT number:  NCT04270760 
 
Amendment Date: 
02 May 2022 
 
Rationale: 
This protocol amendment has two main reasons.  The first one is to reduce the duration of the 
extended safety follow-up period from  40 weeks to a minimum of 24-week follow-up and to 
remove the requirement for the subject’s lipoprotein(a) to return to 80 of baseline levels.  
Based on the non-clinical and first-in-human experience to date, the half-life of olpasiran ranges 
from 4 to 7 hours.  Olpasiran is predominantly eliminated from the systemic circulation within 
2 to 3 days of exposure.  In addition, there was histopathologic evidence of recovery observed 
16 weeks post-treatment in preclinical liver tissue, indicating a low potential for a clinically 
meaningful effect or adverse event.  Thus, a minimum 24-week follow-up after the last 
administered dose is considered appropriate to ensure olpasiran is eliminated from the systemic 
circulation and liver.  Clinical studies have not observed new, residual, or long-lasting adverse 
effects post-administration.  In the sustained absence of exposure to investigational product, 
there is no expected difference in patient safety with the reduced monitoring plan.   
The second reason is to update access to individual subject treatment assignments for Amgen 
(or designee) team members after the treatment period has ended, the database is locked, and 
the snapshot is taken for the end of treatment analysis.  Sites and subjects will be formally 
unblinded after the study is ended, the database is locked, and the snapshot is taken for final 


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  02 May 2022 
Page 2 of 15 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
analysis.  This is to support planning for the phase 3 study.  Additional minor updates were 
incorporated including important clarifications, administrative changes, grammatical corrections, 
and formatting.  Below is a list of the additional important clarifications incorporated in this 
amendment:   
 
Include survival status within General and Safety Assessments in the Schedule of Activities 
to provide clarification and additional guidelines for collection of information (Table 1-1 and 
section 8.2.3.2).  
 
To provide clarification and maintain consistency, the word ‘once’ was added to every 
instance the dosing schedules were defined, QW12 defined as once every 12 weeks and 
Q24W defined as once every 24 weeks (sections 1.1, 2.1, 3, Table 1-2, and Appendix 1). 
 
Incorporate current protocol template language related to recording and reporting of safety 
events in relevant sections of the protocol (Table 1-1, Table 1-2, sections 6.1.5, 8.2.4.1.3, 
and 11.4).    


Product:  Olpasiran 
Protocol Number:  20180109 
Date:  01 April 2021 
Page 1 of 23 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled Phase 2 Study to 
Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) 
(a GalNAc-conjugated Small Interfering RNA [siRNA]) in Subjects With Elevated 
Lipoprotein(a) 
 
Amgen Protocol Number Olpasiran 20180109 
EudraCT number:  2019-003688-23 
NCT number:  NCT04270760 
 
Amendment Date: 
01 April 2021 
 
Rationale: 
The following changes were made to the protocol dated 01 April 2021. 
 
Amended to provide clarification to the wording of the Current Protocol Summary 
Synopsis, Statistical Consideration (Section 1.1), the Study Design, Overall Design 
(Section 4.1), and Number of Subjects (Section 4.2) for the 20180109 study. 
o Updated number of subjects from 240 to 290 and subjects per treatment arm 
from 48 to 58 
o Updated details of the planned Interim Analyses 
o Updated number of subjects per treatment arm in the study schema 
 
Updated administrative edits. 


Product: Olpasiran 
Protocol Number: 20180109   
 
Page 1 of 34 
Amgen Proprietary - Confidential 
Amendment 1 
Protocol Title:  A Double-blind, Randomized, Placebo-controlled Phase 2 Study to 
Evaluate Efficacy, Safety, and Tolerability of Olpasiran (AMG 890) in Subjects With 
Elevated Lipoprotein(a) 
 
Amgen Protocol Number (olpasiran) 20180109 
 
Amendment Date: 
25 November 2020 
 
Rationale: 
The following changes were made to the protocol, dated November 25th, 2020, to 
provide pandemic related guidance, clarify the exclusion criteria regarding the use of 
niacin and fish oil, and to clarify/correct other items in the protocol.  
Pandemic related guidance included:  
 
Addition of telemedicine, paper PRO completion, and home healthcare visits to 
Section 8.1.2. 
Clarification of exclusion criteria regarding niacin and fish oil included:  
 
Modified Exclusion Criterion 218 and added Exclusion Criterion 226 to clarify the 
upper dosage limit for niacin and fish oil.  
Other changes include: 
 
Updated the short protocol title to reflect study name. 
 
Updated Amgen investigational product name. 
 
Clarified laboratory testing, including triglycerides in Section 8.2.5. 
 
Updated statistical consideration to clarify interim analysis for efficacy timeframe. 
 
Updated the schedule of activities to reflect changes in protocol. 
 
Corrected fasting lipid panel within Table 11-1 to appropriate analytes and added 
missing analytes collected. 
 
Modified Exclusion Criterion 203 to clarify the exclusion of inherited or acquired 
known bleeding disorders. 


Product: Olpasiran 
Protocol Number: 20180109   
 
Page 2 of 34 
Amgen Proprietary - Confidential 
 
Updated references and study rationale. 
 
Modified exploratory objectives and endpoints to include achievement of 
Lp(a) < 125 nmol/L. 
 
Updated the number of sites from 50 to 60. 
 
Modified inclusion criterion 103 to clarify fasting Lp(a) threshold during screening.   
 
Updated study treatment period in section 8.1.2 to clarify the day 2 visit window. 
 
Updated safety language in alignment with the current protocol template. 
 
Administration, typographical and formatting changes were made throughout the 
protocol 
 

SAP_001.pdf: 
Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 1 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Statistical Analysis Plan 
 
Protocol Title: 
A Double-blind, Randomized, Placebo-controlled 
Phase 2 Study to Evaluate Efficacy, Safety, and 
Tolerability of Olpasiran (AMG 890) (a GalNAc-
conjugated Small Interfering RNA [siRNA]) in 
Subjects With Elevated Lipoprotein(a) 
Short Protocol Title: 
Olpasiran trials of Cardiovascular Events And 
LipoproteiN(a) reduction – DOSE Finding Study 
(OCEAN[a]-DOSE) 
Protocol Number: 
20180109 
NCT Number: 
NCT04270760 
Authors: 
 
 (PAREXEL) 
 (IQVIA) 
Sponsor: 
Amgen Inc. 
One Amgen Center Drive, Thousand Oaks, CA 
91320, USA 
SAP Date: 
Document Version 
Date 
Original (v1.0) 
Amendment 1 (v2.0) 
Amendment 2 (v2.1) 
14 Oct 2020 
25 Aug 2021 
10 May 2022 
 
 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 2 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
14OCT2020 
 
Amendment 1 (v2.0) 
25AUG2021 
Changes 
1. Change one of the authors from 
 
 
Rationale: Study lead statistician role 
had been transitioned from 
 
 
2. Update statistical analysis plan (SAP) 
version and date throughout this SAP 
Rationale: Statistical analysis plan 
was amended 
3. Change the product name from AMG 
890 to olpasiran throughout this SAP 
Rationale: To align with the Protocol 
Amendment 2 
4. Update the explanation for “AUC” in 
the list of abbreviations 
Rationale: To correct the typo 
5. Remove the abbreviations of “CHD”, 
“NCEP ATP III”, “PT”, “SOC” and 
“TEAE” from the list of abbreviations 
Rationale: These abbreviations are no 
longer relevant to this SAP 
6. Add the explanation for “UC” in the list 
of abbreviations 
Rationale: To explain the abbreviation 
of a new definition added in section 
5.3 
7. Add a level of achievement of Lp(a)  
125 nmol/L in the section 2.1 
Rationale: To align with the Protocol 
Amendment 2 
8. Update the levels of achievement of 
Lp(a)  100 nmol/L to  100 nmol/L, 
Lp(a)  75 nmol/L to  75 nmol/L, 
Lp(a)  50 nmol/L to  50 nmol/L in 
the section 2.1 
Rationale: To align with the Protocol 
Amendment 2 
9. Specify the event types of interests in 
“adjudicated events” in section 2.1 
Rationale: To align with the Protocol 
Amendment 2 
10. Remove the supplement statement of 
“with or without a history of myocardial 
infarction or stroke” from 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 3 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
atherosclerotic cardiovascular disease 
in section 2.2 and 3.1 
Rationale: To align with the Protocol 
Amendment 2 
11. Update the descriptions of interim 
analysis in section 3.1 
Rationale: To align with the Protocol 
Amendment 2 
12. Update the descriptions of sample 
size in section 3.2 
Rationale: To align with the Protocol 
Amendment 2 
13. Update the grouping approach for 
region in section 4.1 
Rationale: To follow the comment 
from TIMI and have the grouping 
consistent in section 4.1 and 4.2 
14. Add a definition for reflexive approach 
in section 5.3 
Rationale: To clarify that how to derive 
the variables of LDL-C and VLDL-C 
by using reflexive approach 
15. Add the definition for CAS in section 
6.2 
Rationale: To clarify the analysis set 
used in sensitivity analysis 
16. Update the descriptions of interim 
analysis in section 7.1 
Rationale: To align with the Protocol 
Amendment 2 
17. Update the wordings from “36-week” 
to “week 36” and from “locked” to 
“processed” in section 7.2 
Rationale: To align with the Protocol 
Amendment 2 
18. Update the wordings from “48-week” 
to “week 48” and from “locked” to 
“processed” in section 7.3 
Rationale: To align with the Protocol 
Amendment 2 
19. Add the approach and analysis set for 
sensitivity analysis in section 9.1 
Rationale: To clarify what test and 
analysis set will be used in sensitivity 
analysis 
20. Add the description for study site will 
be tabulated in section 9.2 
Rationale: To align with the standard 
TFL shells, the number and percent of 
subjects randomized will be provided 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 4 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
21. Update section 9.2 and 9.3 to include 
COVID-19 impact related descriptive 
analysis to measure COVID impact 
Rationale: To describe that the 
COVID-19 related PD will also be 
summarized and listed 
22. Add a sentence for primary in section 
9.5.1 
Rationale: To clarify the sensitivity 
analysis that the primary analysis will 
be performed by completer analysis 
set as well 
23. Update the wording from "treatment" 
to "treatment group" in section 9.5.1 
Rationale: To provide more accurate 
wording in the description 
24. Remove the sentence for log 
transformation in section 9.5.1 
Rationale: Multiple imputation is 
assuming normal distribution, we are 
changing the sensitivity analysis from 
log transformation to a non-parametric 
method 
25. Update the descriptions of additional 
analysis in section 9.5.1 
Rationale: To provide more accurate 
descriptions for MCP-Mod analysis 
26. Add the descriptions for following lipid 
parameters will be provided in section 
9.5.3 
Rationale: Per the suggestions from 
safety team, the descriptive summary 
for HDL-C, non-HDL-C, Triglycerides 
and VLDL-C will be provided as well 
27. Update the MedDRA version in 
section 9.6.1 
Rationale: Per the suggestions from 
safety team and to align with DMP, 
now the MedDRA version is 24.0 
28. Update the descriptions of coding 
term for treatment-emergent adverse 
events in section 9.6.1 
Rationale: Per safety team’s review 
suggestions, TEAEs will be provided 
by PT only; TEAEs, serious TEAEs 
will be tabulated by SOC, HLT and 
PT; TEAEs leading to discontinuation 
of IP, fatal TEAEs, treatment-related 
TEAEs, and treatment-related serious 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 5 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
TEAEs will be provided by SOC and 
PT 
29. Add an adverse events of interest in 
section 9.6.1 
Rationale: Per safety team’s review 
suggestions, adding the “injection site 
reactions” as an new adverse events 
of interest 
30. Update the wording in table tile in 
appendix C 
Rationale: Per the cross-functional 
review team’s suggestions and follow 
up the guideline to change the 
wording from ‘guidelines’ to ‘guideline’ 
 
Amendment 2 (v2.1) 
20APR2022 
Changes 
1. Add one of the authors 
 
Rationale: study statistician has been 
transitioned to 
 
2. Update statistical analysis plan (SAP) 
version and date throughout this SAP 
Rationale: Statistical analysis plan 
was amended 
3. Edited language in Section 3.1 
regarding the extended safety follow-
up period. Removed the language of 
“Only an unblinded team will be 
unblinded at the end of treatment 
period analysis. Individuals who will 
remain involved in the conduct of the 
study will remain blinded” in Section 
7.3. 
Rationale: to align with protocol 
amendment 3 that Amgen team will 
be unblinded after EOT analysis 
snapshot and extended safety follow 
up period will be changed to at least 
24 weeks after week 48. 
4. Add the imputation rule for adverse 
event and concomitant medication 
partial end dates in section 8.3.2 
Rationale: clarifying imputation rule for 
partial end dates to provide more 
clear instruction for programming 
5. Removed the wording “after week 36” 
in section 9.1 
Rationale: EOT analysis will be 
performed including all visits up to 
week 48. 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 6 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
6. Update the summary of analyses 
section for End of Treatment Period 
analysis in Table 2.  
Rationale: analyses for primary 
endpoints will be repeated in EOT 
analysis as well. 
7. Removed the language of biomarker 
endpoint analysis in the section 9.5.3. 
Rationale: Per protocol, the results of 
the exploratory biomarker endpoints 
will not be included in the final clinical 
study report unless noteworthy.  
8. Update the Appendix A analytical visit 
window 
Rationale: 1. add visit window for 
weight and PROMIS Health endpoint 
which were missed in previous SAP. 
2. Added week 72 derivation for non-
lipids/Lp(a) parameters to align with 
protocol amendment 3 that subjects 
are expected to have end of study 
visit on week 72. Changed term 
“EOS” to “> Week 72” 3. Clarified that 
all visits for lipids and Lp(a) will be 
mapped to Q12W windows. 
 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 7 of 37 
CONFIDENTIAL  
 
 
Internal Use Only General Business 
Table of Contents 
Table of Contents ............................................................................................................ 6 
1. 
Introduction ........................................................................................................... 10 
2. 
Objectives, Endpoints and Hypotheses ................................................................. 10 
2.1 
Objectives and Endpoints/Estimands ........................................................ 10 
2.2 
Hypotheses and/or Estimations ................................................................. 13 
3. 
Study Overview .................................................................................................... 13 
3.1 
Study Design ............................................................................................. 13 
3.2 
Sample Size .............................................................................................. 14 
3.3 
Adaptive Design ........................................................................................ 14 
4. 
Covariates and Subgroups ................................................................................... 14 
4.1 
Planned Covariates ................................................................................... 14 
4.2 
Subgroups ................................................................................................. 15 
5. 
Definitions ............................................................................................................. 16 
5.1 
Study Time Points ..................................................................................... 16 
5.2 
Demographics and Baseline Related Definitions ....................................... 17 
5.3 
Other Study Related Definitions ................................................................ 18 
6. 
Analysis Sets ........................................................................................................ 19 
6.1 
Full Analysis Set........................................................................................ 19 
6.2 
Completer Analysis Set ............................................................................. 19 
7. 
Planned Analyses ................................................................................................. 19 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 19 
7.2 
Primary Analysis ....................................................................................... 20 
7.3 
End of Treatment Period Analysis ............................................................. 20 
7.4 
Final Analysis ............................................................................................ 20 
8. 
Data Screening and Acceptance ........................................................................... 21 
8.1 
General Principles ..................................................................................... 21 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 21 
8.3 
Handling of Missing and Incomplete Data ................................................. 21 
8.3.1 
Patterns of Missing Data ........................................................... 21 
8.3.2 
Handling of Incomplete Dates .................................................... 21 
8.4 
Detection of Bias ....................................................................................... 22 
8.5 
Outliers ..................................................................................................... 22 
8.6 
Distributional Characteristics ..................................................................... 22 
8.7 
Validation of Statistical Analyses ............................................................... 23 
9. 
Statistical Methods of Analysis.............................................................................. 23 
9.1 
General Considerations ............................................................................. 23 
9.2 
Subject Accountability ............................................................................... 25 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
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9.3 
Important Protocol Deviations ................................................................... 26 
9.4 
Demographic and Baseline Characteristics ............................................... 26 
9.5 
Efficacy Analyses ...................................................................................... 27 
9.5.1 
Analyses of Primary Efficacy Endpoint ...................................... 27 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 28 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 28 
9.6 
Safety Analyses ........................................................................................ 29 
9.6.1 
Adverse Events ......................................................................... 29 
9.6.2 
Laboratory Test Results ............................................................ 29 
9.6.3 
Vital Signs ................................................................................. 30 
9.6.4 
Physical Measurements ............................................................ 30 
9.6.5 
Electrocardiogram ..................................................................... 30 
9.6.6 
Antibody Formation ................................................................... 30 
9.6.7 
Exposure to Investigational Product .......................................... 30 
9.6.8 
Exposure to Concomitant Medication ........................................ 30 
9.7 
Other Analyses ......................................................................................... 31 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 31 
10. 
Changes From Protocol-specified Analyses.......................................................... 31 
11. 
Literature Citations / References ........................................................................... 31 
12. 
Prioritization of Analyses....................................................................................... 31 
13. 
Data Not Covered by This Plan............................................................................. 31 
14. 
Appendices ........................................................................................................... 32 
Appendix A.  Analytical Study Week Assignments ................................................ 32 
Appendix B.  Common Terminology Criteria for Aes (CTCAE) .............................. 34 
Appendix C.  Lipid Modifying Background Therapy ............................................... 35 
 


Product: Olpasiran 
Protocol Number: 20180109 
Date: 10 May 2022 
Page 9 of 37 
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Internal Use Only General Business 
List of Abbreviations 
 
Abbreviation 
Explanation 
A1C 
Glycated Hemoglobin 
ACC 
American College of Cardiology 
AE 
Adverse Event 
AHA 
American Heart Association 
ALT 
Alanine Aminotransferase 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration Time Curve 
BID 
Twice Daily 
BMI 
Body Mass Index 
CAS 
Completer Analysis Set 
CK 
Creatine Kinase 
Cmax 
Maximum Observed Concentration 
CMH 
Cochran-Mantel Haenszel 
CPMS 
Clinical Pharmacology, Modeling and Simulation 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIIR 
Data Issue Identification and Resolution 
DRT 
Data Review Team 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOIP 
End of Investigational Product 
EOS 
End of Study 
FAS 
Full Analysis Set 
HDL-C 
High-Density Lipoprotein Cholesterol 
hs-CRP 
High Sensitivity C-Reactive Protein 
hs-IL-6 
High Sensitivity Interleukin 6 
IARSC 
Interim Analysis Review Steering Committee 
ID 
Identity 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
IRT 
Interactive Response Technology 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 


Product: Olpasiran 
Protocol Number: 20180109 
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CONFIDENTIAL  
 
 
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LDL-C 
Low-Density Lipoprotein Cholesterol 
LFT 
Liver Function Test 
Lp(a) 
Lipoprotein(a) 
LS means 
Least Square Means 
MCP-Mod 
Multiple Comparison Procedure – Modelling 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCEP ATP III 
National Cholesterol Education Panel Adult Treatment Panel III 
NCT 
National Clinical Trials 
PK 
Pharmacokinetic 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
Q12W 
Every 12 Weeks 
Q24W 
Every 24 Weeks 
QD 
Once Daily 
QoL 
Quality of Life 
QTc 
Corrected QT 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SAS 
Statistics Analysis System 
UC 
Ultracentrifugation 
ULN 
Upper Limit of Normal 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
vs. 
Versus 
WHODrug 
World Health Organization Drug 
 
 


Product: Olpasiran 
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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 2 for study 20180109, 
AMG 890 Olpasiran dated 01 April 2021. The scope of this plan includes the primary 
analysis, the end of treatment period analysis and the final analysis that are planned and 
will be executed by the Amgen Global Biostatistical Science department unless otherwise 
specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints/Estimands 
 
Objectives 
Endpoints 
Primary 
 
To evaluate the effect of olpasiran 
administered subcutaneous (SC) 
every 12 weeks (Q12W) 
compared with placebo, on 
percent change from baseline in 
Lp(a) after 36 weeks of treatment 
 
Percent change in Lp(a) from 
baseline at week 36 
Primary Estimand 
The primary estimand consists of: 
 
The target population, which is adults with atherosclerotic cardiovascular disease 
and elevated Lp(a) 
 
The primary variable, which is percent change from baseline in Lp(a) at week 36 
 
The intercurrent events which are the discontinuation of investigational product 
and excluded medication(s) taken during study. For the primary estimand, the 
treatment effect will be estimated in subjects who are randomized and received 
at least 1 dose of investigational product regardless of the occurrence of these 
intercurrent events 
 
The summary measure, which is the difference between olpasiran and placebo in 
the mean percent change from baseline in Lp(a) at week 36 
 
The treatments to be compared are each olpasiran group vs. placebo 
The primary estimand is the difference between each olpasiran group and placebo in 
the mean percent change from baseline in Lp(a) at week 36 in adults with 
atherosclerotic cardiovascular disease and with elevated Lp(a) who are randomized 
and received at least 1 dose of investigational product, regardless of discontinuation 
of investigational product and excluded medication(s) taken during the study. 
Secondary 
 
To evaluate the effect of olpasiran 
administered SC Q12W compared 
with placebo, on percent change from 
baseline in: 
 Lp(a) after 48 weeks of treatment 
 
Percent change from baseline in: 
 Lp(a) at week 48 
 LDL-C at week 36 and week 48 
 ApoB at week 36 and week 48 


Product: Olpasiran 
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 Low- density lipoprotein 
cholesterol (LDL-C) after 36 and 
48 weeks of treatment 
 Apolipoprotein(B) (ApoB) after 36 
and 48 weeks of treatment 
 
To characterize the pharmacokinetic 
(PK) properties of olpasiran 
 
PK parameters for olpasiran including, 
but not limited to, maximum observed 
concentration (Cmax), and the area 
under the concentration time curve 
(AUC) 
Estimands for Secondary Endpoints 
The estimands for the secondary endpoints in Lp(a), LDL-C, and ApoB are the 
differences between each olpasiran group and placebo in the mean percent change 
from baseline in: 
 
Lp(a) at week 48 
 
LDL-C at week 36 
 
LDL-C at week 48 
 
ApoB at week 36 
 
ApoB at week 48 
For adults with atherosclerotic cardiovascular disease and elevated Lp(a) who are 
randomized and received at least 1 dose of investigational product, regardless of 
discontinuation of investigational product and excluded medication(s) taken during the 
study. 
  
Exploratory 
 
To evaluate the effect of olpasiran 
administered SC Q12W compared with 
placebo, on: 
 percent change from baseline in Lp(a) 
 percent change from baseline in LDL-C 
 percent change from baseline in ApoB 
 achievement of Lp(a) < 125 nmol/L 
 achievement of Lp(a) < 100 nmol/L 
 achievement of Lp(a) < 75 nmol/L 
 achievement of Lp(a) < 50 nmol/L 
 
Percent change from baseline at 
each scheduled visit, except 
weeks 36 and 48, in: 
 Lp(a) 
 LDL-C 
 ApoB 
 
Achievement at each scheduled 
visit of the following: 
 Lp(a) < 125 nmol/L 
 Lp(a) < 100 nmol/L 
 Lp(a) < 75 nmol/L 
 Lp(a) < 50 nmol/L 
 
To evaluate the effect of olpasiran 
administered SC Q24W compared with 
olpasiran administered SC Q12W and 
placebo, on: 
 percent change from baseline in Lp(a) 
 percent change from baseline in LDL-C 
 percent change from baseline in ApoB 
 achievement of Lp(a) < 125 nmol/L 
For the olpasiran SC Q24W group: 
 
Percent change from baseline at 
each scheduled visit, in: 
 Lp(a) 
 LDL-C 
 ApoB 
 
Achievement at each scheduled 
visit of the following: 


Product: Olpasiran 
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 achievement of Lp(a) < 100 nmol/L 
 achievement of Lp(a) < 75 nmol/L 
 achievement of Lp(a) < 50 nmol/L 
 Lp(a) < 125 nmol/L 
 Lp(a) < 100 nmol/L 
 Lp(a) < 75 nmol/L 
 Lp(a) < 50 nmol/L 
 
 
Objectives 
Endpoints 
Exploratory 
 
To estimate cardiovascular event 
rates in subjects treated with 
olpasiran, including aggregated 
exploratory analyses across the 
olpasiran program 
 
Adjudicated events 
 Death by any cause 
 Cardiovascular death 
 Myocardial infarction 
 Hospitalization for unstable angina 
 Coronary revascularization 
 Stroke 
 Transient ischemic attack 
 Cerebrovascular revascularization 
 Acute limb ischemia 
 Major amputation, or urgent 
peripheral revascularization for 
ischemia 
 
To describe the effect of olpasiran of 
quality of life (QoL) measures as 
assessed using the PROMIS Global 
Health 
 
Change from baseline in PROMIS 
Global Health measures at each 
scheduled visit 
 
To evaluate the effect of olpasiran 
administered SC on inflammatory 
biomarkers 
 
Change from baseline at week 48 in: 
 high sensitivity (hs) C-reactive 
protein (CRP) 
 hs-Interleukin 6 (IL-6) 
 
To assess the anti-olpasiran 
antibody response 
 
Anti-olpasiran antibody formation, if 
tested 
Safety 
 
To evaluate the safety and 
tolerability of olpasiran administered 
SC compared with placebo in 
subjects with elevated Lp(a) 
 
Treatment emergent adverse events 
 
Clinically significant safety laboratory 
values and vital signs at each 
scheduled visit 
 
2.2 
Hypotheses and/or Estimations 
The null hypothesis is that there is no difference between olpasiran and placebo in percent 
change from baseline in Lp(a) at week 36 in subjects with atherosclerotic cardiovascular 
disease and with elevated Lp(a). 


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3. 
Study Overview 
3.1 
Study Design 
This is a phase 2, double-blind, randomized, placebo-controlled, multicenter, dose finding 
study to evaluate efficacy, safety, and tolerability of olpasiran on Lp(a) compared to 
placebo in subjects with atherosclerotic cardiovascular disease and with elevated Lp(a). 
Subjects will be randomized in a 1:1:1:1:1 ratio to 1 of the following 5 treatment groups 
(some olpasiran arms will include placebo to maintain blind): 
 
Group 1: 10 mg Q12W 
 
Group 2: 75 mg Q12W 
 
Group 3: 225 mg Q12W 
 
Group 4: 225 mg Q24W 
 
Group 5: Placebo Q12W 
The randomization will be stratified by screening Lp(a) ≤ 200 vs. > 200 nmol/L and by 
region (Japan vs. Non-Japan). 
The study treatment period is 48 weeks with doses at day 1, week 12, week 24, and week 
36. After week 48 there is an extended safety follow-up without further dosing with 
investigational product for a minimum of 24 weeks. Subjects will remain on standard of 
care (including stable lipid-lowering therapy) per their local guidelines during the treatment 
period and extended safety follow-up period. 
An administrative interim analysis will be performed when approximately 240 subjects 
have had the opportunity to complete the week 24 assessments or have early 
terminated. At that point, approximately 120 subjects may have had the opportunity to 
complete the week 36 assessments or have early terminated. 
The interim analysis results will be used to support dose selection for a phase 3 
registrational study and trigger early planning for the phase 3 program. In addition, the 
safety and efficacy results may be used in company internal discussions and external 
interactions with regulatory agencies. The study continues regardless of the administrative 
interim results. 
Team members that remain directly involved with the conduct of the study, investigators 
and subjects will not receive results of the interim analysis and will remain blinded. 


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The primary analysis will occur when all randomized subjects have had the opportunity to 
complete the week 36 assessments or have early terminated. The end of treatment period 
analysis will occur when all subjects have had the opportunity to complete the week 48 
assessments or have early terminated. Final analysis will occur after the last subject either 
completes the extended safety follow-up and has ended the study or has early terminated 
from the study. 
The overall study design is described by a study schema in Section 1.2. in the protocol. 
The endpoints are defined in Section 2.1. 
3.2 
Sample Size 
Assuming standard deviation of 30% as observed in phase 1 study, a 5% drop-out rate 
and with Bonferroni multiplicity adjustment to control family-wise type 1 error rate at 0.05, 
at least 48 subjects per arm provides at least 90% power to detect a treatment difference 
of 25% between an active and placebo arm in mean percent change of Lp(a) from 
baseline. It is expected to have 99% power to detect a treatment effect of -80% vs. -3% 
between active and placebo arms in mean percent change of Lp(a) from baseline. 
Considering 5% drop-out rate, at least 48 subjects per arm (at least 192 subjects in the 4 
active treatment arms) provides a 95% confidence of detecting 1 case of an adverse event 
at an incidence of 1/60. 
Up to a total of approximately 290 subjects may be enrolled. 
3.3 
Adaptive Design 
Not applicable. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
Baseline covariates include, but are not limited to: 
 
Stratification factors 
 Screening Lp(a) (≤ 200 nmol/L vs. >200 nmol/L) 
 Region (Japan vs. Non-Japan) 
 
Age 
 
Sex 
 
Race 
 
Baseline Lp(a) 


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 
Baseline LDL-C 
 
Baseline ApoB 
 
Baseline non-HDL-C 
 
Lipid Lowering Therapy (high intensity, not high intensity) 
 
Region (North America, Europe and Australia, other (including Japan)) 
 
Ethnicity (Hispanic vs. Non-Hispanic) 
4.2 
Subgroups 
Subgroups include, but are not limited to the following: 
 
Stratification factors 
 Screening Lp(a) (≤ 200 nmol/L vs. >200 nmol/L) 
 Region (Japan vs. Non-Japan) 
 
Age (< 65 years, ≥ 65 years) 
 
Sex (male, female) 
 
Race (White, Black, Other) 
 
Baseline Lp(a) by median 
 
Baseline LDL-C by median 
 
Baseline ApoB by median 
 
Baseline non-HDL-C by median 
 
Lipid Lowering Therapy (high-intensity, not high-intensity, as defined in Appendix C) 
 
Region (North America, Europe and Australia, other (including Japan)) 
 
Ethnicity (Hispanic vs. Non-Hispanic) 
If number of subjects in one or more categories is too small (e.g. less than 10%), the 
subgroup categories may be combined. 
5. 
Definitions 
5.1 
Study Time Points 
Enrollment Date 
The enrollment date for each subject is recorded on the Subject Enrollment eCRF. 


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Randomization Date 
Randomization date is defined as the date subject was allocated to a treatment group in 
the interactive response technology (IRT) as recorded on the Subject Enrollment eCRF. 
Study Day 1 
For each subject, Study Day 1 is defined as the date of the first dose of investigational 
product (IP) administration. 
Study Day 
For each subject, and for a given date of interest, study day is defined as the number of 
days since Study Day 1: 
Study Day = (date of interest – Study Day 1 date) +1. 
If the date of interest is prior to the Study Day 1: 
Study Day = (date of interest – Study Day 1 date), so that the day prior to Study Day 1 is 
study day -1. 
First Dose Date of Investigational Product 
For each subject, the First Dose Date of Investigational Product is defined as the date of 
the first administration of IP as recorded on the Investigational Product Administration 
eCRF. 
Last Dose Date of Investigational Product 
For each subject, the Last Dose Date of Investigational Product is defined as the date of 
the last administration of IP as recorded on the Investigational Product Administration 
eCRF. 
End of Treatment Period Date 
For subjects who have week 48 assessment, the End of Treatment Period Date is the 
maximum date of all week 48 assessments. For subjects early withdraw study before 
week 48, the End of Treatment Period Date is the EOS date. ie. End of Treatment 
Period Date is defined as min (maximum date of all week 48 assessments, EOS date).   
Extended Safety Follow-up Period Start Date 
Extended Safety Follow-up Period Start Date = End of Treatment Period Date + 1 
End of Investigational Product (EOIP) Date 


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End of Investigational Product Date is defined as the date of decision was made to end 
investigational product recorded on the End of Investigational Product Administration 
eCRF. 
End of Study (EOS) Date for Individual Subject 
End of Study is defined as the date subject ended study recorded on the End of Study 
eCRF. 
Study End Date for the Overall Study 
The Study End Date is the last EOS date of all randomized subjects. 
5.2 
Demographics and Baseline Related Definitions 
Age 
Age at randomization will be collected as the subject’s age in years at enrollment as 
recorded on the Demographics eCRF. 
Baseline Lipid and Lipid-related Parameters 
Baseline values for Lp(a), lipids (total cholesterol, HDL-C, LDL-C, VLDL-C and 
triglycerides), ApoA1, ApoB, and their derived parameters (eg, ratio between them) are 
defined as the mean of the two most recent non-missing concentrations measured 
through central lab prior to or on study day 1. If for any reason only 1 value is available, 
then that value will be used as baseline. 
Other Baseline Values 
For all other variables, the baseline value is defined as the last non-missing value 
collected prior to or on Study Day 1. 
BMI 
Subject’s BMI will be derived in kg/m2 in the clinical database on the Physical 
Measurement eCRF. 
Change (absolute change) from Baseline 
The arithmetic difference between a post-baseline value and baseline for a given time 
point: 
Change from baseline = (post-baseline value – baseline value) 
Percent Change from Baseline 


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The percent change from baseline for a given variable at a given time point is defined 
as: 
[(value at a given post-baseline time point – baseline value) / baseline value] x 100% 
5.3 
Other Study Related Definitions 
Analytical Study Week Assignments 
Analytical windows will be used to assign parameter measurements to study weeks. The 
algorithm is provided in Appendix A. 
Actual Treatment Group 
A subject’s actual treatment group is the randomized treatment group, unless the subject 
receives treatment throughout the study that is different than the randomized treatment 
group assignment, in which case the actual treatment group is the treatment received. 
Investigational Product (IP) 
Olpasiran SC 10 mg Q12W, 75 mg Q12W, 225 mg Q12W, 225 mg Q24W and placebo 
SC Q12W. 
Study Exposure Period in Months 
For each randomized subject, Study Exposure Period = (EOS date – Randomization 
Date +1) / 365.25 * 12 
IP Exposure Period in Months 
IP Exposure Period = [min (Last IP Dose Date + 84 days, EOS Date) – First IP Dose 
Date + 1] / 365.25 * 12 
Treatment Emergent Adverse Event in Treatment Period 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product as determined by “Did event start before first dose of 
investigational product” equal to No or missing on the Events eCRF and up to the End of 
Treatment Period date, or EOS date for subjects who early discontinue the study during 
the treatment period.  
Treatment Emergent Adverse Event in Extended Safety Follow-up Period 
Events categorized as Adverse Events (AEs) starting on or after first dose of 
investigational product (as determined by “Did event start before first dose of 


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investigational product” equal to No or missing on the Events eCRF) and on or after the 
Extended Safety Follow-up Period Start Date, and up to the EOS date. 
Reflexive Approach for LDL-C and VLDL-C 
Reflexive approach for LDL-C and VLDL-C is only applicable for the central lab data. For 
all analyses related to LDL-C and VLDL-C, unless specified otherwise, the following 
reflexive approach will be used. 
When calculated LDL-C is less than 40 mg/dL or triglycerides are > 400 mg/dL, the 
ultracentrifugation (UC) LDL-C value from the same blood sample will be used instead of 
calculated LDL-C and the UC VLDL-C value from the same blood sample will be used 
instead of calculated VLDL-C, if available. 
6. 
Analysis Sets 
6.1 
Full Analysis Set 
Full analysis set (FAS) includes all randomized subjects who received at least one dose 
of investigational product. 
FAS will be used to perform the efficacy analysis based on randomized treatment group, 
and the safety analysis based on actual treatment group (defined in section 5.3). 
6.2 
Completer Analysis Set 
The completer analysis set (CAS) includes subjects in the FAS who adhered to the 
scheduled IP regimen, and have observed value for the primary endpoint. The completer 
analysis set will be used in sensitivity analysis of the primary endpoint. 
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
An administrative interim analysis will be performed when approximately 240 subjects 
have had the opportunity to complete week 24 assessments or have early terminated. At 
that point, approximately 120 subjects may have had the opportunity to complete week 36 
assessments or have early terminated. The study continues per protocol as planned 
regardless of the data from the administrative interim results. 
Interim analysis results will be reviewed by an Interim Analysis Review Steering 
Committee (IARSC) which consists of internal experts, who are or will thereafter be 
independent of the study team. Further detail regarding the interim analysis process in 
protecting trial integrity is provided in the IARSC Charter. 


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In addition to routine pharmacovigilance monitoring by Amgen, a Data Review Team 
(DRT) has been established to review the accumulating data from this study to ensure 
there is no avoidable increased risk for harm to subjects. The DRT is internal to Amgen 
but external to olpasiran teams. In order to maintain the trial integrity, the unblinded data 
reviewed by the DRT will be restricted and not accessible by the olpasiran team. Further 
detail regarding the DRT is provided in the DRT Charter. 
7.2 
Primary Analysis 
Primary analysis will be performed when all randomized subjects have had the opportunity 
to complete the week 36 assessments or have early terminated. At that time, the database 
related to the primary analyses will be cleaned, processed and a snapshot will be taken. 
Only an unblinded team will be unblinded at the primary analysis. Individuals who will 
remain involved in the conduct of the study will remain blinded. 
7.3 
End of Treatment Period Analysis 
The end of treatment period analysis will be performed when all randomized subjects have 
had the opportunity to complete week 48 assessments or have early terminated. At that 
time, the database related to the end of treatment analyses will be cleaned, processed 
and a snapshot will be taken. 
7.4 
Final Analysis 
Final analysis will be performed when all randomized subjects either complete the 
extended safety follow-up and ended the study or early terminate from the study. At that 
time, the database related to the final analysis will be cleaned, processed and the 
database will be locked. All efficacy and safety analyses during the extended follow-up 
period will be performed. 
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses. This study will use the RAVE 
database. 
All data collected in the eCRF will be extracted from RAVE. Protocol deviations will be 
transferred from eClinical. Final PK data for all randomized subjects will be transferred 


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from statistical programming to Amgen’s CPMS group. Unblinded subject and box ID 
randomization lists will be provided by Amgen’s randomization group and the IVRS when 
the study stops. Details on data transfer will be provided in the Data Transfer Plan. 
8.3 
Handling of Missing and Incomplete Data 
8.3.1 
Patterns of Missing Data 
Subjects may be missing specific data points for various reasons. In general, data may be 
missing due to a subject’s early withdrawal from study, a missed visit, or non-evaluability 
of a data point or an endpoint at a particular point in time. In the Data Issue Identification 
and Resolution (DIIR) processes, queries will be made to the sites to distinguish true 
missing values from other unknown values (eg, due to measurement of sample processing 
error). 
All attempts will be made to capture missing or partial data for this trial prior to the data 
lock. The frequency and pattern of missing data for efficacy endpoints will be assessed 
through descriptive summaries of the measurements over time. 
8.3.2 
Handling of Incomplete Dates 
Adverse event and concomitant medication with completely or partially missing start and 
stop dates will be queried.  
After the issue is queried, if the date is still incomplete with year only or year and month 
only, the start or stop date will be imputed as described in Table 1 below. 
Table 1. Imputation Rules for Incomplete Dates 
 
Missing 
Imputation 
Exception 
Start date (AE and 
concomitant 
medication) 
Day 
1 
Default to Study Day 1 if an event 
starts the same year and month 
as Study Day 1 
Day/Month 
1-Jan 
Default to Study Day 1 if an event 
started the same year as Day 1 
End date (AE and 
concomitant 
medication) 
Day 
Last day of 
the month 
 
 
Day/Month 31-Dec 
 
 
If the stop date is entirely missing, assume the event or medication is ongoing.  


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8.4 
Detection of Bias 
This study has been designed to minimize potential bias by the use of randomization of 
subjects into treatment groups and the use of blinding. It is not expected that any study 
conduct procedures or statistical analyses will introduce bias in the study results or 
conclusions. However, potential sources of bias in this study include: 
 
Major protocol deviations likely to impact the analysis and interpretation of the 
efficacy endpoints 
 
Subject level unblinding before final database lock and formal unblinding 
Important protocol deviations likely to impact the analysis and interpretation of the efficacy 
endpoints will be tabulated in the Clinical Study Report (CSR). 
Any unblinding of individual subjects prior to formal unblinding of the study will be 
documented in the CSR. The impact of such unblinding on the results observed will be 
assessed. 
8.5 
Outliers 
Various methods, including univariate summaries, histograms, scatter plots, box plots, and 
line graphs, may be used to identify outliers in key safety and efficacy variables. Extreme 
data points will be identified during the blinded review of the data prior to database lock. 
Such data points will be reviewed with clinical data management to ensure accuracy. The 
primary analyses will include outliers in the data. Sensitivity analyses may be undertaken 
if extreme outliers for a variable are observed. 
8.6 
Distributional Characteristics 
Distributional assumptions for the planned analyses of the primary and secondary 
endpoints will be assessed. If the assumptions are not met, then alternative methods will 
be utilized. The use of alternative methods will be fully justified in the CSR. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained, and output will be verified in accordance with 
current risk-based quality control procedures. 
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs. 
The production environment for statistical analyses consists of Amgen-supported versions 
of statistical analysis software; for example, the SAS System version 9.4 or later. 


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9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Unless specified otherwise, efficacy analyses will be performed on the FAS by randomized 
treatment group, and safety analyses will be performed on the FAS by actual treatment 
group. 
For the Primary Analysis (as described in Section 7.2), all data up to the primary analysis 
data cut-off date will be included. Based on the snapshot for the primary analysis, efficacy 
and safety analyses will be performed. Testing will be performed for endpoints defined up 
to week 36. Descriptive summary will be provided for all available visits by period (ie. 
Treatment period and extended safety follow-up period). 
For the End of Treatment Period Analysis (as described in Section 7.3), all data up to the 
end of treatment period analysis cut-off date will be included. Testing will be performed for 
endpoints defined up to week 48. Descriptive summary will be provided for all available 
visits by period (ie. Treatment period and extended safety follow-up period). 
For the Final analysis (as described in Section 7.4), all efficacy and safety analyses during 
the extended follow-up period will be performed based on the snapshot for the final 
analysis. 
Subject disposition, demographics, baseline characteristics, and exposure to IP will be 
summarized. 
All categorical variables will be summarized using the number and percent of subjects and 
all continuous variables will be summarized using mean, standard error or standard 
deviation, median, minimum, maximum, and number of subjects with observations. 
Multiplicity Adjustment Method: 
The Hochberg procedure will be used to control the type I error for multiple comparisons 
between active and placebo groups in the primary endpoint. The primary endpoint 
includes percent change in Lp(a) from baseline at week 36 for olpasiran SC Q12W groups 
and placebo. Percent change in Lp(a) from baseline for Q24W group is defined as 
exploratory endpoint. 
A summary of the analyses for each planned analysis can be found in Table 2. 
 
Table 2. Summary of Analyses 


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Analyses Primary Analysis (all 
data up to primary 
analysis data cut-off 
date) 
End of Treatment Period 
Analysis (all data up to 
End of Treatment Period 
Analysis data cut-off 
date) 
Final Analysis (all 
data based on final 
snapshot) 
Efficacy 
 Repeated measures 
model for primary 
endpoint, secondary 
endpoints defined at 
week 36, and 
exploratory endpoints 
of percent change 
from baseline in Lp(a), 
LDL-C and ApoB up 
to week 36. 
 Multiplicity adjustment 
for primary endpoint, 
as described above in 
Multiplicity Adjustment 
Method 
 Sensitivity analysis for 
primary endpoint 
using non-parametric 
(Quade test) approach 
based on CAS 
 Cochran-Mantel 
Haenszel (CMH) test 
adjusted by the 
stratification factors 
will be used for 
exploratory endpoints 
of Lp(a) achievements 
 Repeated measures 
model for primary 
endpoint, secondary 
endpoints defined at 
week 36 and week 48 
and exploratory 
endpoints of percent 
change from baseline in 
Lp(a), LDL-C and ApoB 
up to week 48. Testing 
is performed up to 
week 48. 
 Multiplicity 
adjustment for 
primary endpoint, as 
described above in 
Multiplicity 
Adjustment Method 
 Sensitivity analysis 
for primary endpoint 
using non-parametric 
(Quade test) approach 
based on CAS 
 Cochran-Mantel 
Haenszel (CMH) test 
adjusted by the 
stratification factors will 
 Descriptive 
summary for 
efficacy endpoints 
in the extended 
follow-up period 


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(including 
achievement of Lp(a) 
< 125nmol/L) up to 
week 36 
Descriptive summary 
for all efficacy 
endpoints by period 
(ie. Treatment period 
and extended safety 
follow-up period) 
be used for exploratory 
endpoints of Lp(a) 
achievements 
(including achievement 
of Lp(a) < 125nmol/L) 
up to week 48 
 Descriptive summary 
for all efficacy 
endpoints by period (ie. 
Treatment period and 
extended safety follow-
up period) 
Safety 
 Summary by actual 
treatment group by 
period (ie. Treatment 
period and extended 
safety follow-up 
period) 
 Summary by actual 
treatment group by 
period (ie. Treatment 
period and extended 
safety follow-up period) 
 Summary by actual 
treatment group in 
the extended 
follow-up period  
 
9.2 
Subject Accountability 
The number of subjects screened, randomized, receiving IP, and completing the study will 
be summarized by randomized treatment group. Key study dates for the first subject 
enrolled, last subject enrolled and last subject’s end of study will be presented. 
Study discontinuation and IP discontinuation will be tabulated separately by reasons for 
discontinuation, including due to COVID-19 impact if applicable. 
The number and percent of subjects randomized will be tabulated by study site, the 
stratification factors. 
The number of subjects included in and excluded from each analysis set and reason for 
exclusion will also be summarized. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before the 
first subject’s initial visit and updated during the IPD reviews throughout the study prior to 


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database lock.  These definitions of IPD categories, subcategory codes, and descriptions 
will be used during the course of the study. Eligibility deviations are defined in the protocol. 
The number of subjects reporting Protocol Deviations due to COVID-19 impact will be 
summarized in a table. A Protocol Deviation listing of subjects impacted due to COVID-19 
will also be provided. 
9.4 
Demographic and Baseline Characteristics 
All baseline tables will be summarized by randomized treatment group and overall using 
descriptive statistics. Baseline tables will summarize demographics, baseline 
characteristics, targeted medical history, and lipid regulating medication. If multiple races 
have been reported for a subject, the subject will be categorized as multiple race. 
Difference in stratum assignment between IVRS/IWRS stratum and data-derived stratum 
will be tabulated. 


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9.5 
Efficacy Analyses 
9.5.1 
Analyses of Primary Efficacy Endpoint 
To assess the primary endpoint of the mean percent change from baseline at week 36 in 
Lp(a), a repeated measures linear mixed effects model including terms for treatment 
group, stratification factors, scheduled visit and the interaction of treatment group with 
scheduled visit will be used. The least squares means (LS means) by treatment group and 
the treatment difference (olpasiran - placebo) at week 36 based on the model above will 
be summarized. The Hochberg procedure will be used to control the type I error for 
multiple comparisons between active and placebo groups. 
To evaluate the robustness of the analysis results, sensitivity analyses will be performed 
as follow: 
 
The primary analysis will be repeated using CAS. 
 
Non-parametric analyses (Quade test) will be performed based on CAS 
 
To evaluate the impact of missing data, multiple imputation for subjects who 
discontinue IP with missing endpoint data: 
o It will be assumed that the missing percent change values will be normally 
distributed with a mean zero and a variance-covariance matrix the same 
as the observed variance-covariance matrix from subjects in the placebo 
group who did not discontinue IP with missing endpoint data. 
o If there is sufficient number of subjects in each treatment group who 
discontinue IP but have non-missing endpoint data, an additional multiple 
imputation will be carried out utilizing the information from these subjects 
to impute the missing data for subjects who discontinue IP and have 
missing endpoint data. 
Additional analysis for percent change in Lp(a) from baseline at week 36 of all dose groups 
(Q12W and Q24W) will be performed using Multiple Comparison Procedure - Modelling 
(MCP-Mod) methodology (Bretz et al, 2005). MCP-Mod is a hybrid approach that 
combines hypothesis testing and modeling in a structured manner to analyze phase 2 
dose-ranging studies with the purpose of finding target dose(s) of interest and provide 
guidance for suitable dose(s) entering the confirmatory phase 3 trials. The first step of the 
procedure (MCP-step) is used to assess presence of a dose response signal using a trend 
test deducted from a set of prespecified candidate models. The prespecified candidate 


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dose response models will be selected based on the known pharmacology and Lp(a) 
reduction of Olpasiran from phase I trials. The second step (Mod-step) relies on parametric 
modeling or model averaging to find the “optimal” dose for confirmatory trials. MCP-Mod 
method is found more effective than pairwise comparison due to its ability to utilize all 
available data from the continuum of active doses and placebo to estimate a parametric 
dose response curve which allows for interpolation and extrapolation of effect across a 
range of doses (Dinko Rekic et al, 2015). 
Covariate analyses of the primary endpoint will be performed. Baseline covariates listed 
in Section 4.1 in their original format, will be included one at a time, in the repeated 
measures model used in the primary analysis. 
Subgroup analyses on the primary efficacy endpoint will be conducted using the 
subgroups specified in Section 4.2. Treatment effect differences among subgroups, which 
represent subgroup by treatment interactions, will be estimated and tested based on 
statistics from the subgroup repeated measures models. 
For covariate and subgroup analyses, the data-derived stratification factors will be used. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Analysis of the secondary endpoints (including percent change from baseline at week 36 
in ApoB and LDL-C, and percent change from baseline at week 48 in ApoB, Lp(a) and 
LDL-C) will be performed similarly to the analysis of the primary endpoint. There will be 
no multiplicity adjustment for the secondary efficacy endpoints. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Exploratory endpoints of percent change from baseline at scheduled visits in Lp(a), LDL-
C and ApoB will be analyzed using repeated measures linear effects model including 
terms for treatment group, stratification factors, scheduled visit and the interaction of 
treatment group with scheduled visit will be used; and achievements of Lp(a) at scheduled 
visits (including achievement of Lp(a) < 125nmol/L) will be analyzed using CMH test as 
specified in Table 2. Subject incidence of positively adjudicated events (overall and by 
event type as defined in protocol) and change from baseline in PROMIS Global Health 
measures at scheduled visits will be summarized by treatment group using descriptive 
statistics. 
Descriptive summary for non-HDL-C, HDL-C, VLDL-C and Triglycerides will be provided 
by scheduled visits. 


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9.6 
Safety Analyses 
9.6.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or later will be 
used to code all events categorized as adverse events to a system organ class and a 
preferred term. All adverse event tables will be summarized by actual treatment group. All 
adverse event summaries will include all treatment-emergent events reported on the Event 
eCRF, including CEC reviewed events. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, adverse events leading to withdrawal of 
investigational product, and fatal adverse events. 
Subject incidence of all treatment-emergent adverse events will be provided by preferred 
term in descending order of frequency. Treatment-emergent adverse events and 
treatment-emergent serious adverse events will be tabulated by system organ class, high 
level term, and preferred term in descending order of frequency. Treatment-emergent 
adverse events leading to discontinuation of investigational product, treatment-emergent 
fatal adverse events, treatment-related treatment-emergent adverse events, and 
treatment-related treatment-emergent serious adverse events will be provided by system 
organ class, and preferred term in descending order of frequency. 
Subject incidence of adverse events of interest (peripheral neuropathy, myopathy, 
hypersensitivity reactions, effects on renal and liver function, hyperglycemia (including 
new onset diabetes), thrombocytopenia, coagulation parameters, immune-inflammatory 
and injection site reactions) will be summarized by category and preferred term. 
9.6.2 
Laboratory Test Results 
Selected laboratory parameters will be summarized using descriptive statistics at 
scheduled visits. Laboratory shift tables using the CTCAE v5.0 or later grading will be 
used for analytes of interest, when applicable. The results will be based on the maximum 
(e.g., worst) shift from baseline to the EOS.  
In addition, creatine kinase (CK) and liver function test (LFT) abnormalities will be 
assessed by the incidence overall and by visits of the following categories: 
 
CK > 5 x ULN 
 
CK > 10 x ULN 
 
ALT or AST > 3 x ULN 
 
ALT or AST > 5 x ULN 


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 
Total bilirubin > 2 x ULN 
 
(ALT or AST > 3 x ULN) and Total bilirubin > 2 x ULN and Alkaline Phosphatase 
<2 x ULN 
9.6.3 
Vital Signs 
Vital signs will be summarized using descriptive statistics at each scheduled visit by actual 
treatment group. 
9.6.4 
Physical Measurements 
Physical measurements will be summarized using descriptive statistics at each scheduled 
visit by actual treatment groups. 
9.6.5 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of assessment 
of potential QT interval corrected (QTc) effect.  Since these evaluations may not 
necessarily be performed under the rigorous conditions expected to lead to meaningful 
evaluation of QTc data; neither summaries nor statistical analyses will be provided, and 
these data would not be expected to be useful for meta-analysis with data from other trials. 
9.6.6 
Antibody Formation 
Anti-olpasiran binding antibodies will be summarized descriptively, if applicable. Subject 
level listing may be provided instead of summary if there is a small number of subjects 
that are tested for anti-olpasiran antibodies. 
9.6.7 
Exposure to Investigational Product 
The exposure to IP will be summarized using descriptive statistics by actual treatment 
group. 
9.6.8 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving medications of interest will be summarized 
by preferred term or category for each treatment group as coded by the World Health 
Organization Drug (WHODrug) dictionary. 
9.7 
Other Analyses 
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
A PK sub-study will be conducted with a total of approximately 75 subjects (approximately 
15 from each treatment cohort). A maximum of 3 samples may be collected at additional 
time points during the study if warranted and agreed upon between the investigator and 


Product: Olpasiran 
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the sponsor. Pharmacokinetic samples will be collected as per the PK sub-study schedule 
of assessments (see protocol Table 1-1 and Table 1-2). 
Individual and summary statistics for PK concentrations will be provided. These analyses 
will be performed by the CPMS group for the primary analysis, the end of treatment period 
analysis, and final analysis. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 
11. 
Literature Citations / References 
Bach JP, Riedel O, Pieper L, et al. Health-related quality of life in patients with a history 
of myocardial infarction and stroke. Cerebrovasc Dis. 2011;31:68-76. 
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics. 2005;61(3):738-748. 
Grundy SM, Stone NJ, Bailey AL, et al. 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on 
the management of blood cholesterol: a report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 
Circulation. 2018; 139: e1046-e1081. 
Dinko Rekic, Yaning Wang, Vikram Sinha. Request for Qualification of MCP-Mod as an 
efficient statistical methodology for model-based design and analysis of Phase II dose 
finding studies under model uncertainty. 22 April, 2015 
12. 
Prioritization of Analyses 
Not applicable. 
13. 
Data Not Covered by This Plan 
Not applicable. 


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14. 
Appendices 
Appendix A.  Analytical Study Week Assignments 
Selected endpoints will be summarized by scheduled study visits in descriptive analyses. 
Since the actual visits may not exactly coincide with their scheduled visit day, the actual 
visit day is mapped to the study visit generally by non-overlapping consecutive intervals 
covering the entire time continuum. The mapping intervals for all distinct schedules are 
summarized in the following table. 
 
Handling multiple records assigned to an analytical study week: 
If there is more than one record in a study week interval, the analytical record for that 
specific study week will be defined as the record closest to the scheduled visit day of 
that specific study week (7 x study week + 1). If two records are equidistant from the 
scheduled day, then the earlier record will be chosen. If there are multiple records on the 
same day, the last record will be used. 
 
 


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Analytical 
Study 
Week 
Scheduled 
Visit Day 
Physical, Neurological, and Muscular 
Examination, Vital Signs, Urine 
Pregnancy Test, Anti-Olpasiran-
Antibody, PROMIS General Health 
Physical 
measurement 
(weight only) 
Fasting Lipids and 
Lp(a) 
Glucose, ApoA1, ApoB, VLDL-C, 
Coagulation, Hematology, Hemoglobin 
A1C, Chemistry including hs-CRP, 
eGFR, Urinalysis 
Day 2 
2 
 
 
(1, 15] 
 
Week 4 
29 
 
 
(15, 42] 
(1, 56] 
Week 8 
57 
 
 
(42, 70] 
 
Week 12 
85 
(1, 126] 
 
(70, 98] 
(56, 126] 
Week 16 
113 
 
 
(98, 126] 
 
Week 20 
141 
 
 
(126, 154] 
 
Week 24 
169 
(126, 210] 
 
(154, 182] 
(126, 210] 
Week 28 
197 
 
 
(182, 210] 
 
Week 32 
225 
 
 
(210, 238] 
 
Week 36 
253 
(210, 294] 
 
(238, 266] 
(210, 294] 
Week 40 
281 
 
 
(266, 294] 
 
Week 44 
309 
 
 
(294, 322] 
 
Week 48 
337 
(294, 420] 
(1, 420] 
(322, 378] 
(294, 420] 
Week 60 
421 
 
 
(378, 462] 
 
Week 72 
505 
(420, 546] 
(420, 546] 
(462, 546] 
(420, 546]  
Week 84 
589 
 
 
(546, 630] 
 
Q12Wa 
n*71 
 
 
((n-6)*7, (n6)*7] 
 
> Week 72 
Scheduled 
visit day 
> 546 
> 546 
-b 
> 546 
 
a For Q12W scheduled visit, week n can have possible values of 9612*m, where m0, 1, 2, 3, … until the subject has completed 
study or subject has discontinued from the study. 
b For Lipids and Lp(a), all visits occurred after week 84 will be mapped to Q12W window.  


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Product: Olpasiran 
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Appendix B.  Common Terminology Criteria for Aes (CTCAE) 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 is 
modified for laboratory shift table. The CTCAE is available at the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
 


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Appendix C.  Lipid Modifying Background Therapy 
Based on modified ACC/AHA 2018 guideline: 
 
High-Intensity Lipid 
Lowering Therapy 
Moderate-Intensity Lipid 
Lowering Therapy 
Low-Intensity Lipid 
Lowering Therapy 
Atorvastatin 
≥ 40 mg QD 
10 – < 40 mg QD 
< 10 mg QD 
Rosuvastatin 
≥ 20 mg QD 
5 – < 20 mg QD 
< 5 mg QD 
Simvastatin 
≥ 80 mg QD 
20 – < 80 mg QD 
< 20 mg QD 
Pravastatin 
 
≥ 40 mg QD 
< 40 mg QD 
Lovastatin 
 
≥ 40 mg QD 
< 40 mg QD 
Fluvastatin XL 
 
80 mg QD 
< 80 mg QD 
Fluvastatin 
 
40 mg BID 
< 40 mg BID 
Pitavastatin 
 
1 – 4 mg QD 
< 1 mg QD 
 
If a subject is on PCSK9 inhibitor, it will be considered as high intensity. 
If a subject is on statin (high or moderate intensity, or at low intensity for Atorvastatin or 
Rosuvastatin)  Ezetimibe 10mg QD, it will be considered as high intensity. 
If a subject is on low intensity statin (for Simvastatin, Pravastatin, Lovastatin, Fluvastatin 
XL, Fluvastatin, or Pitavastatin)  Ezetimibe 10mg QD, it will be considered as moderate 
intensity. 
If Ezetimibe 10mg QD only, it will be considered as low intensity. 
If a subject is on Bempedoic acid 180 mg QD without statin, it will be considered as low 
intensity. 
If a subject is on Bempedoic acid 180 mg QD with statin, it will be considered as high 
intensity. 
If a subject is on Ezetimibe 10mg QD and Bempedoic acid 180 mg QD, it will be 
considered as moderate intensity. 
If a subject is not on any Lipid Lowering Therapy, it will be considered as no lipid 
lowering therapy.