A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of LY3819469 in Adults With Elevated Lipoprotein(a)
Phase: PHASE2
Conditions: Lipoprotein Disorder
Sponsor: Eli Lilly and Company

Protocol J3L-MC-EZEB Initial Protocol 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of LY3819469 in Adults With Elevated Lipoprotein(a) 
NCT05565742
Approval Date: 19-Jul-2022

CONFIDENTIAL 
J3L-MC-EZEB 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3819469, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of LY3819469 in Adults with Elevated Lipoprotein(a) 
Protocol Number: J3L-MC-EZEB 
Amendment Number: This is the initial protocol. 
Compound: LY3819469 
Brief Title:  
Efficacy and safety of LY3819469 compared with placebo in adults with elevated Lp(a) 
Study Phase: 2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 154938 
EU trial number: 2022-501426-38-00 
Document ID: VV-CLIN-068490 
Approval Date: Protocol Electronically Signed and Approved by Lilly on date provided below. 
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J3L-MC-EZEB 
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Medical Monitor Name and Contact Information will be provided separately. 
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Table of Contents 
1.
Protocol Summary ..........................................................................................................6
1.1.
Synopsis ............................................................................................................................6
1.2.
Schema ..............................................................................................................................9
1.3.
Schedule of Activities (SoA) ..........................................................................................10
2.
Introduction ...................................................................................................................18
2.1.
Study Rationale ...............................................................................................................18
2.2.
Background .....................................................................................................................18
2.2.1.
Introduction to Lp(a) .......................................................................................................18
2.2.2.
Elevated Levels of Lp(a) Are Associated with Increased Risk of 
Cardiovascular Disease ...................................................................................................19
2.2.3.
Available Treatments ......................................................................................................20
2.2.4.
Introduction to LY3819469 ............................................................................................20
2.3.
Benefit/Risk Assessment ................................................................................................20
2.3.1.
Risk Assessment .............................................................................................................20
2.3.2.
Benefit Assessment .........................................................................................................21
2.3.3.
Overall Benefit Risk Conclusion ....................................................................................21
3.
Objectives, Endpoints, and Estimands .......................................................................22
4.
Study Design ..................................................................................................................24
4.1.
Overall Design ................................................................................................................24
4.2.
Scientific Rationale for Study Design ............................................................................24
4.2.1.
Participant Input into Design ..........................................................................................25
4.3.
Justification for Dose ......................................................................................................25
4.4.
End of Study Definition ..................................................................................................25
5.
Study Population ...........................................................................................................26
5.1.
Inclusion Criteria ............................................................................................................26
5.2.
Exclusion Criteria ...........................................................................................................27
5.3.
Lifestyle Considerations .................................................................................................28
5.3.1.
Meals and Dietary Restrictions .......................................................................................28
5.3.2.
Blood Donation ...............................................................................................................29
5.4.
Screen Failures ................................................................................................................29
5.5.
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................29
6.
Study Intervention(s) and Concomitant Therapy .....................................................30
6.1.
Study Intervention(s) Administered................................................................................30
6.2.
Preparation, Handling, Storage, and Accountability ......................................................31
6.3.
Measures to Minimize Bias: Randomization and Blinding ............................................31
6.4.
Study Intervention Compliance ......................................................................................32
6.5.
Dose Modification ..........................................................................................................32
6.6.
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................32
6.7.
Treatment of Overdose ...................................................................................................32
6.8.
Concomitant Therapy .....................................................................................................32
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34 
7.1. 
Discontinuation of Study Intervention ............................................................................34 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................35 
7.1.2. 
QTc Stopping Criteria .....................................................................................................36 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................36 
7.3. 
Lost to Follow-up............................................................................................................37 
8. 
Study Assessments and Procedures.............................................................................38 
8.1. 
Efficacy Assessments .....................................................................................................38 
8.1.1. 
Primary Efficacy Assessment .........................................................................................38 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................38 
8.2. 
Safety Assessments .........................................................................................................38 
8.2.1. 
Electrocardiograms .........................................................................................................38 
8.2.2. 
Clinical Safety Laboratory Tests ....................................................................................38 
8.2.3. 
Hepatic Safety .................................................................................................................39 
8.2.4. 
Hepatitis B Testing and Monitoring ...............................................................................41 
8.2.5. 
Hepatitis C Testing .........................................................................................................41 
8.2.6. 
Injection Site Reactions ..................................................................................................42 
8.2.7. 
Hypersensitivity Reactions .............................................................................................42 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................42 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................43 
8.3.2. 
Pregnancy ........................................................................................................................45 
8.3.3. 
Major Adverse Cardiovascular Events ...........................................................................46 
8.4. 
Pharmacokinetics ............................................................................................................46 
8.5. 
Pharmacodynamics .........................................................................................................47 
8.6. 
Genetics ..........................................................................................................................47 
8.7. 
Biomarkers ......................................................................................................................47 
8.8. 
Immunogenicity Assessments.........................................................................................47 
8.9. 
Health Economics ...........................................................................................................47 
9. 
Statistical Considerations .............................................................................................48 
9.1. 
Statistical Hypotheses .....................................................................................................48 
9.1.1. 
Multiplicity Adjustment ..................................................................................................48 
9.2. 
Analyses Sets ..................................................................................................................48 
9.3. 
Statistical Analyses .........................................................................................................48 
9.3.1. 
General Considerations ...................................................................................................48 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................48 
9.3.3. 
Secondary Endpoint(s)/Estimand(s) Analysis ................................................................49 
9.3.4. 
Exploratory Endpoint(s) Analysis...................................................................................49 
9.3.5. 
Safety Analyses ...............................................................................................................49 
9.3.6. 
Pharmacokinetic and Pharmacodynamic Analyses ........................................................50 
9.3.7. 
Immunogenicity Assessments .........................................................................................51 
9.3.8. 
Subgroup Analyses .........................................................................................................51 
9.4. 
Interim Analysis ..............................................................................................................51 
9.5. 
Sample Size Determination ............................................................................................52 
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10. 
Supporting Documentation and Operational Considerations ..................................53 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................53 
10.1.1. Regulatory and Ethical Considerations ...........................................................................53 
10.1.2. Financial Disclosure........................................................................................................54 
10.1.3. Informed Consent Process ..............................................................................................54 
10.1.4. Data Protection................................................................................................................54 
10.1.5. Committees Structure......................................................................................................55 
10.1.6. Dissemination of Clinical Study Data.............................................................................55 
10.1.7. Data Quality Assurance ..................................................................................................55 
10.1.8. Source Documents ..........................................................................................................57 
10.1.9. Study and Site Start and Closure ....................................................................................57 
10.1.10. Publication Policy ...........................................................................................................58 
10.1.11. Investigator Information .................................................................................................58 
10.1.12. Sample Retention ............................................................................................................58 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................59 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................62 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................64 
10.3.1. Definition of AE .............................................................................................................64 
10.3.2. Definition of SAE ...........................................................................................................65 
10.3.3. Definition of Product Complaints ...................................................................................66 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................66 
10.3.5. Reporting of SAEs ..........................................................................................................68 
10.3.6. Regulatory Reporting Requirements ...............................................................................69 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................70 
10.4.1. Definitions.......................................................................................................................70 
10.4.2. Contraception Guidance..................................................................................................70 
10.5. 
Appendix 5: Genetics......................................................................................................72 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................73 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................75 
10.8. 
Appendix 8: Abbreviations and Definitions ...................................................................79 
11. 
References ......................................................................................................................84 
 
 
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J3L-MC-EZEB 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title:  
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of LY3819469 in Adults with Elevated Lipoprotein(a)  
Brief Title:  
Efficacy and safety of LY3819469 compared with placebo in adults with elevated Lp(a)  
Regulatory Agency Identifier Number(s):  
IND: 154938 
EU trial number: 2022-501426-38-00 
Rationale: 
Elevated lipoprotein(a) (Lp[a]) is recognized as an important risk factor for cardiovascular 
disease; there are currently no approved pharmaceutical interventions for lowering Lp(a). 
LY3819469 is a novel Dicer-substrate small interfering ribonucleic acid (siRNA) oligonucleotide 
designed to reduce the levels of LPA mRNA and apolipoprotein(a) (Apo[a]) expression and 
thereby to decrease Lp(a). In Phase 1 Study J3L-MC-EZEA, single subcutaneous (SC) doses of 
LY3819469 significantly and durably decreased Lp(a) and no safety issues were identified. This 
Phase 2 study aims to investigate the impact of a range of LY3819469 doses on Lp(a) level and 
on safety in a larger population of participants with elevated Lp(a) to enable Phase 3 
development of this compound. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
 To evaluate if LY3819469 is superior to 
placebo in percent Lp(a) reduction 
 Percent change from baseline in 
time-averaged Lp(a) over Days 60-
180 
Secondary 
 
 To evaluate if LY3819469 is superior to 
placebo in percent Lp(a) reduction over 
Days 240-360 
 Percent change from baseline in 
time-averaged Lp(a) over Days 240-
360 
 Compare proportion of participants on 
LY3819469 versus placebo achieving 
Lp(a) threshold levels 
 Proportion of participants achieving 
Lp(a) <125 and <75 nmol/L at Days 
60, 180, 240, 360, and 540 
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Objectives 
Endpoints 
 Compare the effect of LY3819469 to 
placebo on cardiovascular biomarkers 
 Percent change from baseline to 
Days 60, 180, 240, 360, and 540 for 
o Lp(a) 
o ApoB 
o hsCRP 
 Characterize the PK of LY3819469 
 Population PK parameters 
Abbreviations: ApoB = apolipoprotein B; hsCRP = high-sensitivity C-reactive protein; Lp(a)_= lipoprotein(a); 
PK = pharmacokinetics. 
Estimands 
The primary clinical question of interest is: What is the study intervention difference in percent 
change from baseline in time-averaged Lp(a) over Days 60-180 of study intervention in 
participants who meet the enrollment criteria regardless of treatment discontinuation for any 
reason? 
A similar estimand as the estimand for the primary objective will be used for the secondary 
objectives. 
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3819469 doses with placebo irrespective of adherence to study intervention. 
Overall Design 
Study is a parallel, double-blinded, placebo-controlled, dose-finding, Phase 2 study of 
LY3819469 in participants with elevated Lp(a). 
Approximately 254 participants will be randomized in a 1:2:2:2:2 ratio to 1 of the following 
arms: 
 Arm A: 16-mg LY3819469, doses at randomization and Day 180 
 Arm B: 96-mg LY3819469, doses at randomization and Day 180 
 Arm C: 400-mg LY3819469, doses at randomization and Day 180 
 Arm D: 400-mg LY3819469, dosed at randomization, placebo at Day 180 
 Arm E: placebo, doses at randomization and Day 180 
Brief Summary: 
The purpose of this study is to measure difference in percent change from baseline in time-
averaged Lp(a) on over Days 60-180 with LY3819469 versus placebo in participants with 
elevated Lp(a). 
Study details include: 
● The study duration will be up to 20 months. 
● The treatment duration will include doses at the randomization visit and at Day 180. 
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Study Population: 
The study will include adults at least 40 years old. People in the study who are on particular 
medicines should stay on the same doses for the whole study. People who have had a major 
illness or surgery in the 3 months prior to the study will not participate. People who have certain 
abnormal laboratory values will not be included. 
Number of Participants: 
Approximately 254 participants will be randomly assigned to study intervention. 
Intervention Groups and Duration: 
All participants will receive a subcutaneous injection at the randomization visit and at Day 180 
(Visit 7). LY3819469 is formulated at a concentration of 160 mg/mL.  
Arm A 
Arm B 
Arm C 
Arm D 
Arm E 
Intervention Name 
LY3819469 
LY3819469 
LY3819469 
LY3819469 
and Placebo 
Placeboa 
Dosage #1 
 
 
 
 
 
LY3819469 Solution 
(160mg/mL) 
16 mg 
(0.1 mL) 
96 mg 
(0.6 mL) 
400 mg 
(2.5 mL) 
400 mg 
(2.5 mL) 
− 
Placebo (0.9% sodium 
chloride solution for 
injection) 
− 
− 
− 
− 
Placeboa 
Dosage #2 
 
 
 
 
 
LY3819469 Solution 
(160mg/mL) 
16 mg 
(0.1 mL) 
96 mg 
(0.6 mL) 
400 mg 
(2.5 mL) 
− 
− 
Placebo (0.9% sodium 
chloride solution for 
injection) 
− 
− 
− 
Placebob 
Placeboa 
Route of Administration 
SC injection 
SC injection 
SC injection 
SC injection 
SC injection 
Authorized as defined by 
EU Clinical Trial 
Regulation 
Not 
authorized in 
EU 
Not 
authorized in 
EU 
Not 
authorized in 
EU 
Not authorized 
in EU 
Not authorized 
in EU 
Abbreviations: EU = European Union; SC = subcutaneous. 
a Participants in Arm E will be randomly assigned so that each dose cohort will have a matching placebo cohort 
that receives the same dose volume to maintain the study blind. 
b Participants in Arm D will receive a 2.5-ml placebo dose at Day 180 (Visit 7). 
Ethical Considerations of Benefit/Risk: 
Based on current information, the study medicine treatment is believed to have more benefits 
than risks. 
Data Monitoring Committee: No 
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J3L-MC-EZEB 
 
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1.2. 
Schema 
 
 
 
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J3L-MC-EZEB 
 
10 
1.3. 
Schedule of Activities (SoA) 
Period I - Optional Prescreening: The study includes an optional prescreening visit (Visit 601) as a simple way for sites to determine 
whether participants meet Lp(a) criteria, as assessed by a central laboratory assessment, before the full screening activities are initiated 
at Visit 1. If the participant has not had Lp(a) measured before or is unknown, the prescreening visit should be completed. The 
prescreening visit can be conducted at the study site, or remotely, for example, at a mobile healthcare or alternate laboratory. The 
prescreening determination of Lp(a) will be described in an appropriate informed consent form (ICF). Informed consent for the 
prescreening activities will be obtained, a participant identification number will be assigned, and sample for the Lp(a) prescreening 
laboratory test will be obtained. The optional prescreening visit can be repeated 1 time (no more) per participant if the investigator 
believes the participant would meet criteria at a later time, with a minimum of 4 weeks between visits. Repeated sampling in the 
prescreening visit will not require re-consenting or assignment of a new participant identification number. Note: If the optional 
prescreening is opted for, central laboratory testing for Lp(a) is still required as part of the screening procedures conducted at Visit 1. 
Participants with Lp(a) <175 nmol/L at Visit 1 will not be eligible for enrollment, despite their values in prescreening. A prescreening 
visit occurring longer or shorter than 21 days (3 weeks) from screening will not be considered a protocol deviation. 
Period II - Screening: Visit 1 procedures may be conducted over more than 1 day as long as all activities are completed prior to Visit 
2. 
Period III - Treatment and Assessment Period: All procedures (screening and baseline) need to be completed prior to the first dose of 
study intervention. For an early discontinuation (ED) from the study intervention that occurs before the last visit in treatment period, 
see the activities listed for ED in this table. 
 
 
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11 
   
Period I - 
Pre-
Screening  
Period II 
- 
Screening  
Period III -– Treatment and Assessment Period 
Participants are required to fast before 
Visits 1-12. See Section 5.3.1. If a 
participant arrives not fasted, schedule 
the laboratory draw for another date. 
Visit number 
601 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
 
Days from 
randomization 
≤42 
≤21 
— 15 
30 
60 
120 
180 
210 
240 
300 
360 
540 
 
Visit 1 procedures may be conducted 
over more 
than 1 day if all activities are 
completed within 
the allowable visit tolerance. 
Visit interval 
tolerance (days) 
See Section 
1.3 
— 
— ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
--- 
 
Prescreening 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Informed 
consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
The ICF must be signed before any 
protocol-specific tests or procedures 
are performed. 
See Appendix 10.1.3 for additional 
details. 
Inclusion and 
exclusion 
criteria, review 
and confirm 
 
X 
X 
  
  
  
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria should 
be confirmed prior to drug assignment 
and administration of first dose of 
study intervention.  
Ascertainment of 
high risk for 
cardiovascular 
events 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
High risk for cardiovascular events 
will be defined as CAD, stroke, or 
peripheral artery disease, or ASCVD 
risk equivalents (familial 
hypercholesterolemia or type 2 
diabetes) 
Demographics 
  
X 
  
  
  
  
 
 
 
 
 
 
 
 
Includes year of birth, sex, ethnicity 
(where permissible), and race. 
Preexisting 
conditions and 
medical history, 
including 
relevant surgical 
history 
  
X 
  
  
  
  
 
 
 
 
 
 
 
 
All conditions ongoing and relevant 
past surgical and medical history 
should be collected.  
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12 
   
Period I - 
Pre-
Screening  
Period II 
- 
Screening  
Period III -– Treatment and Assessment Period 
Participants are required to fast before 
Visits 1-12. See Section 5.3.1. If a 
participant arrives not fasted, schedule 
the laboratory draw for another date. 
Visit number 
601 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
 
Days from 
randomization 
≤42 
≤21 
— 15 
30 
60 
120 
180 
210 
240 
300 
360 
540 
 
Visit 1 procedures may be conducted 
over more 
than 1 day if all activities are 
completed within 
the allowable visit tolerance. 
Visit interval 
tolerance (days) 
See Section 
1.3 
— 
— ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
--- 
 
Prespecified 
medical history 
(indication and 
history of 
interest)  
  
X 
  
  
  
  
 
 
 
 
 
 
 
 
Prespecified medical history includes 
history of cardiovascular events. 
Prior treatments 
for indication 
  
X 
  
  
  
  
  
  
 
 
 
 
 
 
Relevant prior therapies include, but 
are not limited to, lipid-lowering 
medications. 
Substance use 
(alcohol, 
caffeine, and 
tobacco use)  
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
  
Concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Additional data will be collected for 
medications of interest. 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Any events that occur after signing the 
informed consent are considered AEs 
as defined (Appendix 10.3). 
Additional data are collected for 
certain AEs. 
Physical 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Height  
  
X 
  
  
  
  
  
  
 
 
 
 
 
 
Participant should remove shoes. 
Weight  
 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Participant should remove shoes. 
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13 
   
Period I - 
Pre-
Screening  
Period II 
- 
Screening  
Period III -– Treatment and Assessment Period 
Participants are required to fast before 
Visits 1-12. See Section 5.3.1. If a 
participant arrives not fasted, schedule 
the laboratory draw for another date. 
Visit number 
601 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
 
Days from 
randomization 
≤42 
≤21 
— 15 
30 
60 
120 
180 
210 
240 
300 
360 
540 
 
Visit 1 procedures may be conducted 
over more 
than 1 day if all activities are 
completed within 
the allowable visit tolerance. 
Visit interval 
tolerance (days) 
See Section 
1.3 
— 
— ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
--- 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes pulse rate and blood pressure 
measured after participant has been 
sitting at least 5 minutes and before 
ECG tracing and collection of blood 
samples for laboratory testing.  
Physical 
examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 X 
X 
The physical examination is 
performed (excludes pelvic, rectal, 
and breast examinations unless 
clinically indicated). 
Symptom-
directed physical 
assessment 
 
 
X 
 
 
Symptom-directed physical 
assessment will be conducted at the 
discretion of the PI or qualified 
personnel, per local regulations, as 
indicated based on participant status 
and standard of care. 
12-Lead ECG 
(local) 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Collect single, local ECG prior to 
collection of blood samples for 
laboratory testing, including PK 
samples. Participants should be supine 
for approximately 5 to 10 minutes 
before ECG collections and remain 
supine but awake during the ECG 
collection. ECGs may be repeated at 
the PI’s discretion at any visit. See 
Section 8.2.1. 
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14 
   
Period I - 
Pre-
Screening  
Period II 
- 
Screening  
Period III -– Treatment and Assessment Period 
Participants are required to fast before 
Visits 1-12. See Section 5.3.1. If a 
participant arrives not fasted, schedule 
the laboratory draw for another date. 
Visit number 
601 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
 
Days from 
randomization 
≤42 
≤21 
— 15 
30 
60 
120 
180 
210 
240 
300 
360 
540 
 
Visit 1 procedures may be conducted 
over more 
than 1 day if all activities are 
completed within 
the allowable visit tolerance. 
Visit interval 
tolerance (days) 
See Section 
1.3 
— 
— ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
--- 
 
Laboratory 
Tests and 
Sample 
Collections 
  
  
  
  
  
  
  
  
 
 
  
 
 
 
 
 
 
  
Hematology  
  
X 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
  
Clinical 
chemistry  
  
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
  
Lipid panel 
  
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
  
Urinalysis  
  
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
  
UACR 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Serum 
pregnancy 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Females only.  
FSH 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Optional; performed as needed to 
confirm postmenopausal status. See 
Appendix 10.4. 
TSH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Lp(a) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
ApoB 
  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
hsCRP 
  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
HIV screening 
test 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
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Period I - 
Pre-
Screening  
Period II 
- 
Screening  
Period III -– Treatment and Assessment Period 
Participants are required to fast before 
Visits 1-12. See Section 5.3.1. If a 
participant arrives not fasted, schedule 
the laboratory draw for another date. 
Visit number 
601 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
 
Days from 
randomization 
≤42 
≤21 
— 15 
30 
60 
120 
180 
210 
240 
300 
360 
540 
 
Visit 1 procedures may be conducted 
over more 
than 1 day if all activities are 
completed within 
the allowable visit tolerance. 
Visit interval 
tolerance (days) 
See Section 
1.3 
— 
— ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
--- 
 
HCV screening 
test 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
If HCV antibody test is positive, it 
must be followed by an HCV RNA 
test. See Section 8.2.5.  
HBV screening 
test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
If HBsAg is negative and HBcAb is 
positive, further testing with HBV 
DNA is required. If the screening 
HBV DNA is negative, the participant 
is not excluded. See Section 8.2.4.  
eGFR 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Calculated using CKD-EPI method.  
Postdose PK 
sample  
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Visit 2: Collect 2 samples. 
 
0.5 hours postdose 
 
4-9 hours postdose 
(minimum 2 hours) 
Visit 7: Collect 1 sample. 
1. 24-36 hours postdose, will 
require participant to return 
1 day after Visit 7. 
Immunogenicity 
(ADA) 
 
 
P 
X 
X 
 
X 
P 
 
X 
 
X 
X 
X 
Visit 2 and 7 will be collected 
predose. 
PK sample for 
immunogenicity 
 
 
 
X 
X 
 
X 
P 
 
X 
 
X 
X 
X 
Collect a time-matched PK sample for 
all scheduled and unscheduled 
immunogenicity 
samples.  
Visit 7 will be collected predose. 
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Period I - 
Pre-
Screening  
Period II 
- 
Screening  
Period III -– Treatment and Assessment Period 
Participants are required to fast before 
Visits 1-12. See Section 5.3.1. If a 
participant arrives not fasted, schedule 
the laboratory draw for another date. 
Visit number 
601 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
 
Days from 
randomization 
≤42 
≤21 
— 15 
30 
60 
120 
180 
210 
240 
300 
360 
540 
 
Visit 1 procedures may be conducted 
over more 
than 1 day if all activities are 
completed within 
the allowable visit tolerance. 
Visit interval 
tolerance (days) 
See Section 
1.3 
— 
— ±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
±7 
±14 
--- 
 
Stored Samples 
  
  
  
  
  
  
  
  
 
 
  
 
 
 
On dosing days, collect samples 
before dosing 
Optional 
genetics sample 
  
  
X 
 
 
 
 
 
 
 
 
 
 
 
Sample can be obtained at or after the 
specified visit. See Appendix 10.5. 
Exploratory 
biomarker 
samples  
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
  
Randomization 
and Dosing 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Register visit 
with IWRS 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Unscheduled visits are not required to 
be registered in IWRS. 
Randomization 
via IWRS  
  
  
X 
 
 
 
 
 
 
 
 
 
 
 
  
Dispense study 
intervention via 
IWRS 
  
  
X 
 
 
 
 
X 
 
 
 
 
 
 
  
Administer study 
intervention 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
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Abbreviations: ACC/AHA = American College of Cardiology/American Heart Association; ADA = anti-drug antibody; AE = adverse event; ApoB = 
apolipoprotein b; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CKD-EPI = Chronic Kidney Disease Epidemiology 
Collaboration; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ED = early discontinuation; eGFR = estimated glomerular filtration rate; FSH = 
follicle-stimulating hormone; HbA1c = hemoglobin A1c; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; ICF = informed consent form; IWRS = 
Interactive Web-Response System; Lp(a) = Lipoprotein(a); P = predose; PI = principal investigator; PK = pharmacokinetic; RNA = ribonucleic acid; TSH = 
thyroid stimulating hormone; UACR = urine albumin creatinine ratio. 
 
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2. 
Introduction 
LY3819469 is a novel Dicer-substrate small interfering ribonucleic acid (siRNA) oligonucleotide 
designed to reduce the levels of LPA mRNA and apolipoprotein(a) (Apo[a]) expression and 
thereby to decrease lipoprotein(a) (Lp[a]). LY3819469 is being developed to reduce the risk of 
cardiovascular events in patients with or at high risk of atherosclerotic cardiovascular disease 
(ASCVD) and high levels of Lp(a) 
2.1. 
Study Rationale 
Elevated Lp(a) is recognized as an important risk factor of cardiovascular disease; there are 
currently no approved pharmaceutical interventions for lowering Lp(a). LY3819469 is an 
siRNA, that decreases Lp(a) formation and has been shown to reduce Lp(a) in preclinical studies. 
In Phase 1 Study J3L-MC-EZEA (EZEA) with single doses of LY3819469, Lp(a) was 
significantly decreased and no safety issues were identified. This Phase 2 study aims to 
investigate the impact of a range of LY3819469 doses on Lp(a) level and on safety in a larger 
population of participants with elevated Lp(a) to enable Phase 3 development of this compound. 
2.2. 
Background 
2.2.1. 
Introduction to Lp(a) 
Lp(a) is an atherogenic lipoprotein consisting of a low-density lipoprotein particle linked via a 
disulfide bond to Apo(a) (see Figure 1). 
Apo(a) is a protein found in new-world monkeys, great apes, and humans (Utermann 1989). The 
protein, encoded by the LPA gene, includes 10 unique units of kringle IV repeats; the first and 
third through tenth are present in single copies while the second is present in variable copy 
numbers (1 to <50). Additionally, the protein includes a kringle V and a protease-like domain 
that is not biologically active (Dubé et al. 2012; Kronenberg and Utermann 2013; Tsimikas 
2017). 
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Abbreviations: Apo(a) = apolipoprotein(a); ApoB = apolipoprotein b; LDL = low-density lipoprotein; 
Lp(a) = lipoprotein(a). 
 
Figure 1. 
Representation of Lp(a) particle. 
Lp(a) contains oxidized phospholipids. Plasma levels of Lp(a) are genetically determined. 
Single-nucleotide polymorphisms (SNPs) of the LPA gene are associated with higher or lower 
Lp(a) levels; for example, rs10455872 and rs3798220 are associated with increased Lp(a) 
(Clarke et al. 2009; Li et al. 2011). Additionally, the number of kringle IV2 repeats determines 
protein size, which is inversely proportional to plasma concentration and mass of Lp(a); larger 
Apo(a) size is associated with lower concentrations of Lp(a). Despite this genetically induced 
variability in Lp(a) concentrations between individuals, intra-patient variability in Lp(a) is low 
and is not thought to be materially impacted by diet, environmental factors, or exercise (Schmidt 
et al. 2016). However, Apo(a) is an acute-phase reactant, and Lp(a) increases, for example, after 
surgery, myocardial infarction, and infection (Maeda et al. 1989; Noma et al. 1994; Min et al. 
1997). 
2.2.2. 
Elevated Levels of Lp(a) Are Associated with Increased Risk of Cardiovascular 
Disease 
Lp(a) particles are thought to exert adverse cardiovascular effects through atherogenic, 
inflammatory, and possibly pro-thrombotic activity (Tsimikas 2017). 
In a meta-analysis of 36 studies, Lp(a) was associated with risk for nonfatal myocardial 
infarction or coronary death (Emerging Risk Factors Collaboration et al. 2009). In studies of 
LPA gene KIV2 repeats or SNPs, genetic variants conferring higher levels of Lp(a) were found 
to be related to risk for myocardial infarction and coronary disease in Mendelian randomization 
and genome-wide association studies (Clarke et al. 2009; Kamstrup et al. 2009). In a study 
including data from the United Kingdom (UK) Biobank, 7 genome-wide association studies, and 
LPA sequencing, Lp(a) was associated with risk of coronary heart disease, stroke, chronic kidney 
disease, aortic valve stenosis, heart failure, and peripheral vascular disease (Emdin et al. 2016). 
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The American Heart Association and American College of Cardiology Guideline on the 
management of blood cholesterol defined Lp(a) ≥50 mg/dL or ≥125 nmol/L as risk enhancing in 
2018 (Grundy et al. 2019). Elevated Lp(a) >50 mg/dL was present in 24% of samples from a 
reference laboratory and 29.2% of samples from a tertiary care center (Varvel et al. 2016). The 
estimated prevalence of Lp(a) >60 mg/dL is 64 million in the United States, 150 million in 
Europe, and 1.4 billion worldwide (Tsimikas and Stroes 2020). 
2.2.3. 
Available Treatments 
Lipid apheresis is approved and used in some geographies for patients with elevated Lp(a) 
(Jaeger et al. 2009; Nugent et al. 2020). Proprotein convertase subtilisin/kexin type 9 (PCSK9) 
inhibitors, alirocumab, evolocumab, and inclisiran, reduce Lp(a) by approximately 25% 
(Robinson et al. 2015; Sabatine et al. 2015; Stoekenbroek et al. 2019), and prescription-strength 
niacin also produces 15% to 25% reductions in Lp(a) (AIM-HIGH Investigators 2011; HPS2-
THRIVE Collaborative Group 2014), but are not approved treatments for Lp(a) reduction. Novel 
treatments to reduce Lp(a) are under investigation, including an antisense oligonucleotide 
(pelacarsen), and 2 siRNA therapies (olpasiran and SLN360), which have been shown to lower 
Lp(a) concentrations in clinical trials (Viney et al. 2016; Tsimikas et al 2020; Ference 2022; 
Koren et al. 2022; Nissen et al. 2022). 
2.2.4. 
Introduction to LY3819469 
LY3819469 inhibits the production of Apo(a) by causing degradation of LPA mRNA through the 
siRNA mechanism. LY3819469 reduces steady-state levels of Apo(a) protein in a mouse model 
transgenic for human Apo(a), and Lp(a) in cynomolgus monkeys that endogenously express 
Lp(a). 
Nonclinical toxicology studies of LY3819469 showed no notable adverse drug effects.  
In Phase 1 Study EZEA of participants treated with single LY3819469 doses up to 608 mg, 
Lp(a) was lowered and no notable adverse drug effects were observed.  
Efficacy will be determined by measuring circulating levels of Lp(a) in this Phase 2 study to 
enable dose selection for Phase 3 study.  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of LY3819469 may be found in the Investigator’s Brochure (IB) 
or Development Safety Update Report.  
2.3.1. 
Risk Assessment 
Study Intervention 
The pharmacodynamic (PD) effect of LY3819469 is anticipated to be lowering of Lp(a). Lp(a) 
serves no known positive functions and is not present in most species. Additionally, people 
homozygous for null mutations of the LPA gene have not been identified to have any related 
health issues. Furthermore, toxicology studies of LY3819469 have shown no notable adverse 
effects. Finally, human Phase 1 Study EZEA showed that single LY3819469 doses up to 608 mg 
were safe and generally well tolerated by healthy male and female participants.  
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Study Procedures 
The study will include blood draws and safety monitoring, and these procedures are not 
anticipated to be associated with significant participant risk. 
2.3.2. Benefit Assessment 
Lp(a) is a lipoprotein particle with atherogenic, inflammatory, and possibly pro-thrombotic 
activity. In preclinical studies and a previous Phase 1 study, LY3819469 decreased Lp(a). 
Lowering of Lp(a) is anticipated to have beneficial effects on cardiovascular disease; however, 
the duration of lowering of Lp(a) in this study may not be sufficient to confer any benefits. 
Nevertheless, participants may benefit by receiving personal health information from the 
physical examinations and from other routine safety assessments performed in this study. 
2.3.3. Overall Benefit Risk Conclusion 
Treatment with study intervention is anticipated to have an acceptable benefit to risk profile. 
 
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3. 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
 
 To evaluate if LY3819469 is superior 
to placebo in percent Lp(a) reduction 
 Percent change from baseline in time-
averaged Lp(a) over Days 60-180 
Secondary 
 
 To evaluate if LY3819469 is superior 
to placebo in percent Lp(a) reduction 
over Days 240-360 
 Percent change from baseline in time-
averaged Lp(a) over Days 240-360 
 Compare proportion of participants on 
LY3819469 versus placebo achieving 
Lp(a) threshold levels 
 Proportion of participants achieving 
Lp(a) <125 and <75 nmol/L at Days 
60, 180, 240, 360, and 540 
 Compare the effect of LY3819469 to 
placebo on cardiovascular biomarkers 
 Percent change from baseline to Days 
60, 180, 240, 360, and 540 for 
o Lp(a) 
o ApoB 
o hsCRP  
 Characterize the PK of LY3819469  
 Population PK parameters  
Exploratory 
 
 To evaluate if LY3819469 is superior 
to placebo in absolute change from 
baseline 
 Absolute change from baseline in 
Lp(a) at Days 60, 180, 240, 360, and 
540 
 Compare proportion of participants on 
LY3819469 versus placebo achieving 
absolute lowering of Lp(a) threshold 
 Proportion of participants achieving 
Lp(a) lowering of at least 150 nmol/L 
at Days 60, 180, 240, 360, and 540 
 Compare the lipid profile in response 
to LY3819469 versus placebo 
 Lipid profile 
o LDL-C 
o total cholesterol 
o HDL-C 
o triglycerides 
 Evaluation of immunogenicity.  
 Incidence of treatment-emergent 
ADAs.  
Abbreviations: ADA = anti-drug antibody; ApoB = apolipoprotein B; HDL-C = high-density lipoprotein-
cholesterol; hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein-cholesterol; 
Lp(a) = Lipoprotein(a); PK = pharmacokinetics. 
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Primary estimand 
The primary clinical question of interest is: What is the intervention difference in percent change 
from baseline in time-averaged Lp(a) over Days 60-180 of study intervention in participants who 
meet the inclusion criteria regardless of treatment discontinuation for any reason? 
The primary estimand characterizes the treatment effect regardless of intercurrent events and is 
named the “treatment-regimen estimand.” 
The treatment-regimen estimand is described by the following attributes: 
Population: participants who meet the enrollment criteria. Further details can be found in Section 
5. 
Endpoint: percent change from baseline in time-averaged Lp(a) over Days 60-180 which will be 
calculated by area under the curve (AUC) between Day 60 to Day 180 divided by 120. 
Treatment condition: the randomized treatment with allowance for safety. Further details on 
study interventions, and concomitant interventions can be found in Section 6.  
There are no intercurrent events. Since each patient can only take one dose for the first 6 months, 
there is no intercurrent events of treatment discontinuation. The concomitant medication use is 
not considered intercurrent events as it is considered as a part of patient management.  
Population-level summary: mean percent changes in Lp(a). 
Treatment contrast of interest: difference in mean percent changes in Lp(a) between LY3819469 
and placebo. 
Rationale for estimand: this estimand aims to study the efficacy of LY3819469 that reflects the 
real-life behavior of the target population. 
Estimand(s) for secondary objective 
A similar estimand for the primary objective will be used for the secondary clinical response 
before the second injection at Day 180. For the objectives after Day 180, the treatment 
discontinuation will be handled by treatment policy strategy.  
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3819469 doses with placebo irrespective of adherence to study intervention. 
 
 
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4. 
Study Design 
4.1. 
Overall Design 
Study EZEB is a parallel, double-blinded, placebo-controlled, dose-finding, Phase 2 study of 
LY3819469 in participants with elevated Lp(a). 
Approximately 254 participants will be randomized in a 1:2:2:2:2 ratio to 1 of the following 
arms: 
 Arm A: 16-mg LY3819469 dosed at randomization and Day 180 
 Arm B: 96-mg LY3819469 dosed at randomization and Day 180 
 Arm C: 400-mg LY3819469 dosed at randomization and Day 180 
 Arm D: 400-mg LY3819469 dosed at randomization, and placebo at Day 180 
 Arm E: placebo doses at randomization and Day 180 
Treatment periods and assessments are described in the Schedule of Activities (SoA) (Section 
1.3) 
The study schema is shown in Section 1.2. 
The study population is described in Section 5.  
The efficacy and safety assessments are described in Sections 8.1 and 8.2, respectively. 
4.2. 
Scientific Rationale for Study Design 
Interim data from Phase 1 Study EZEA showed a decrease in Lp(a) in healthy participants with 
Lp(a) levels ≥75 nmol/L or ≥30 mg/dL given single doses of LY3819469. The current study is 
intended to be Phase 3 enabling, as it will provide the following information: 
 Efficacy and safety data with subcutaneous (SC) administration of doses of study drug at 
randomization and Day 180 in participants with higher levels of Lp(a). This design is 
anticipated to provide information regarding the maximal level and durability of lowering 
of Lp(a) with LY3819469 and information regarding an appropriate dose and dosing 
frequency of study drug for Phase 3. The primary endpoint is over Days 60-180 to assess 
the lowering of Lp(a) across time. 
 Participants for this study will have Lp(a) ≥175 nmol/L at baseline. This study will thus 
provide relevant efficacy and safety for participants with Lp(a) sufficiently high to 
participate in a Phase 3 cardiovascular outcomes trial. 
The study includes an optional prescreening Visit 601 where potential participants can be 
prescreened with an assessment of Lp(a). 
Participants qualifying based on the optional prescreening assessment and those known to have a 
significantly elevated Lp(a) can be screened for inclusion in the trial at Visit 1. 
Placebo is chosen as the control treatment to assess whether any observed effects are treatment 
related or simply reflect the study conditions. The double-blind design minimizes bias. 
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In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. This question can be answered only if all the relevant data are collected. 
4.2.1. Participant Input into Design 
Throughout this protocol, the term "participant" is used to indicate an individual who participates 
in a clinical trial, either as a recipient of an investigational intervention or as a control. This 
usage reflects preferences indicated by patient advocates to more accurately reflect the role of 
people who take part in clinical trials. 
4.3. 
Justification for Dose 
LY3819469 doses of 16 mg, 96 mg, and 400 mg, administered subcutaneously, were selected 
based on the following: 
 Safety and tolerability of LY3819469 doses up to 608 mg in healthy participants in the 
Phase 1 Study EZEA 
 The selected dose levels and dose range support a robust dose-exposure–response 
analysis of multiple safety and efficacy measures to support selection of dose(s) of 
LY3819469 with optimal benefit/risk ratio for further clinical development 
4.4. 
End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit or the last scheduled procedure shown in the SoA. 
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5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
Presence or absence of high risk for cardiovascular events will be a factor for stratification of the 
randomization. High risk for cardiovascular events will be defined as coronary artery disease 
(CAD), stroke, or peripheral artery disease, or ASCVD risk equivalents (familial 
hypercholesterolemia or type 2 diabetes).  
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be at least 40 years old at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants with Lp(a) ≥175 nmol/L at Visit 1, measured at the central laboratory. 
3. Participants on the following medications according to local practice must be on a stable 
regimen for at least 4 weeks prior to Visit 1 and expected to remain on a stable regimen 
through the end of the Treatment and Assessment Period: 
a. lipid-lowering drugs (such as statins, ezetimibe, PCSK9 inhibitors, prescription-
dose niacin, fibrates, fish oil, or other products containing omega-3 fatty acids, 
including over-the-counter [OTC] preparations) 
b. testosterone, estrogens, anti-estrogens, progestins, selective estrogen receptor 
modulators, or growth hormone 
Weight 
4. Have a body mass index within the range 18.5 to 40 kg/m2, inclusive. 
Sex and Contraceptive/Barrier Requirements 
5. Male and/or female  
a. Males who agree to use highly effective/effective methods of contraception may 
participate in this trial.  
b. Women of childbearing potential (WOCBP) are excluded from the trial. 
c. Women not of childbearing potential (WNOCBP) may participate in this trial.  
Please refer to Appendix 10.4 for definitions and additional guidance related to 
contraception. 
Contraceptive use by participants should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. For the 
contraception requirements of this protocol, see Appendix 10.4. 
Informed Consent 
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6. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
Other Inclusions 
7. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures, in the opinion of the investigator. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
8. Have a history or presence of an underlying disease, or surgical, physical, medical, or 
psychiatric condition that, in the opinion of the investigator, would potentially affect 
participant safety within the study or interfere with participating in or completing the 
study or with the interpretation of data. 
9. Any of the following, or other events indicating unstable medical condition in the opinion 
of the investigator, within 3 months of Visit 1: 
a. major surgery 
b. coronary, carotid, or peripheral arterial revascularization 
c. stroke or transient ischemic attack 
d. myocardial infarction or unstable angina 
e. acute limb ischemia. 
10. Have, in the 6 months prior to Visit 1, uncontrolled Type 1 or Type 2 diabetes, defined as 
an episode of ketoacidosis or hyperosmolar state requiring hospitalization, or have a 
hemoglobin A1c (HbA1c) ≥8% at Visit 1. 
11. Have uncontrolled hypertension with a resting blood pressure ≥160 mm Hg systolic 
and/or ≥100 mm Hg diastolic at Visit 1; a repeat measure is allowed. 
12. New York Health Association Class III or IV heart failure or last known left ventricular 
ejection fraction <30%. 
13. Active or acute infection requiring systemic antiviral or antimicrobial therapy that will 
not be completed prior to Visit 2. 
14. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated. 
15. Recent history of, or current drug or alcohol abuse in the opinion of the investigator. 
16. Have 2 or more clinically significant or severe drug allergies, or severe post-treatment 
hypersensitivity reactions, including, but not limited to 
f. erythema multiforme major 
g. linear immunoglobulin A dermatosis 
h. toxic epidermal necrolysis 
i. exfoliative dermatitis. 
17. Hypersensitivity to the active substance or to any of the excipients. 
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18. Have a current infection with hepatitis B virus (HBV), that is, positive for hepatitis B 
surface antigen (HBsAg) and/or polymerase chain reaction (PCR) positive for HBV 
deoxyribonucleic acid (DNA) (Section 8.2.4). 
19. Have a current infection with hepatitis C virus (HCV), that is, positive for HCV 
ribonucleic acid (RNA) (Section 8.2.5). 
20. Have human immunodeficiency virus (HIV) infection. 
Prior/Concomitant Therapy 
21. Lipoprotein apheresis within 3 months of Visit 1, or planned during the study. 
22. Treatment with another investigational drug, biological agent, or device within 1 month 
of Visit 1, or 5 half-lives of investigational agent, whichever is longer. 
23. Treatment with any oligonucleotide or siRNA within 9 months of Visit 1. 
Prior/Concurrent Clinical Study Experience 
24. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
Diagnostic Assessments 
25. Clinically significant abnormalities in screening laboratory values that would render a 
participant unsuitable for inclusion in the opinion of the investigator. 
26. Any of the following abnormalities: 
a. estimated glomerular filtration rate (eGFR) ˂30 mL/min/1.73 m2 
b. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0x upper 
limit of normal (ULN) 
c. bilirubin > 1.5x ULN, except for participants diagnosed with Gilbert’s syndrome 
Other Exclusions 
27. Are Eli Lilly and Company (Lilly) employees, or are employees of any third party 
involved in a study that requires exclusion of their employees. 
28. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted. 
29. Are pregnant, or intend to become pregnant or to breastfeed during the study. 
30. Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at 
significant risk for suicide. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
Participants are required to fast for at least 10 hours before Visits 1-12. Routine blood chemistry 
and urine samples should be taken after fasting for at least 10 hours. Fasting is not required for 
postdose pharmacokinetic (PK) samples. During preparation for fasting samples, the participant 
can drink water and they should ensure that they consume sufficient water in order to not become 
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dehydrated. It is not necessary to fast for Visit 601, PK blood draws, or for any confirmatory test, 
or test taken for safety reasons; these may be taken without regard to fasting status. 
5.3.2. 
Blood Donation 
Participants must not donate blood for the duration of the study. 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once if the investigator believes the participant would meet criteria at a later time. 
Rescreened participants should be assigned a new participant number for every screening or 
rescreening event. 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention of 
a Participant 
Not applicable. 
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6. 
Study Intervention(s) and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.  
6.1. 
Study Intervention(s) Administered 
Arm A 
Arm B 
Arm C 
Arm D 
Arm E 
Intervention Name 
LY3819469 
LY3819469 
LY3819469 
LY3819469 
and Placebo 
Placeboa 
Dosage #1 
 
 
 
 
 
LY3819469 Solution (160 
mg/mL) 
16 mg 
(0.1 mL) 
96 mg 
(0.6 mL) 
400 mg 
(2.5 mL) 
400 mg 
(2.5 mL) 
− 
Placebo (0.9% sodium 
chloride solution for 
injection)  
− 
− 
− 
− 
Placeboa 
Dosage #2 
 
 
 
 
 
LY3819469 Solution (160 
mg/mL) 
16 mg 
(0.1 mL) 
96 mg 
(0.6 mL) 
400 mg 
(2.5 mL) 
− 
− 
Placebo (0.9% sodium 
chloride solution for 
injection) 
− 
− 
− 
Placebob 
Placeboa 
Route of Administration 
SC injection 
SC injection 
SC injection 
SC injection 
SC injection 
Authorized as defined by 
EU Clinical Trial 
Regulation 
Not 
authorized in 
EU 
Not 
authorized in 
EU 
Not 
authorized in 
EU 
Not 
authorized in 
EU 
Not 
authorized in 
EU 
Abbreviations: EU = European Union; SC = subcutaneous. 
a Participants in Arm E will be randomly assigned so that each dose cohort will have a matching placebo cohort 
that receives the same dose volume to maintain the study blind. 
b Participants in Arm D will receive a 2.5-ml placebo dose at Day 180 (Visit 7). 
The table below describes the injection volume for the different intervention dose groups. 
Intervention Group  
Injection volume  
16 mg or matched placebo participants  
0.1 mL  
96 mg or matched placebo participants  
0.6 mL  
400 mg or matched placebo participants  
2.5 mL 
 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
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6.2. 
Preparation, Handling, Storage, and Accountability 
1. The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention. Only authorized 
study personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized study personnel. 
3. The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
will be provided separately.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally assigned to randomized study intervention using an Interactive 
Web-Response System (IWRS). Participants will be stratified by high risk for cardiovascular 
events (yes/no) and baseline Lp(a) (<275 nmol/L, ≥275 nmol/L). Placebo participants will be 
randomly assigned so that each dose cohort will have a matching placebo cohort that receives the 
same dose volume to maintain the study blind. Before the study is initiated, the log in 
information and directions for the IWRS will be provided to each site. 
Study intervention will be dispensed and administered at the study visits summarized in SoA. 
This is a double-blind study in which participants are blinded to study intervention. The IWRS 
will be programmed with blind-breaking instructions. In case of an emergency, the investigator 
has the sole responsibility for determining if unblinding of a participants’ intervention 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact the sponsor prior to unblinding a participant’s intervention 
assignment unless this could delay emergency treatment for the participant. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified immediately within 24 hours 
of this occurrence. The date and reason that the blind was broken must be recorded. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant may be continued in the study. 
Investigators will remain blinded to each participant’s assigned study intervention throughout the 
course of the study. To maintain this blind, an otherwise uninvolved third party will be 
responsible for the preparation and dispensation of all study intervention and will endeavor to 
ensure that there are no differences in time taken to dispense following randomization. 
This third party will instruct the participant to avoid discussing the volume of injection, dosing 
frequency, or packaging of the study intervention with the investigator. 
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In the event of a quality assurance audit, the auditor(s) will be allowed access to unblinded study 
intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
6.4. 
Study Intervention Compliance 
Study intervention will be administered under medical supervision by the investigator or 
designee. The study intervention and study participant identification will be confirmed prior to 
the time of dosing. The date and time of each dose administered will be recorded in the source 
documents and in the case report form (CRF). 
6.5. 
Dose Modification 
This protocol does not allow dose adjustments. 
6.6. 
Continued Access to Study Intervention after the End of the Study 
LY3819469 will not be made available to participants after completion of the study. 
6.7. 
Treatment of Overdose 
For this study, any dose of LY3819469 greater than the planned dose will be considered an 
overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator/treating physician should: 
● Contact the medical monitor immediately. 
● Evaluate the participant to determine, in consultation with the medical monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
● Closely monitor the participant for any AE/SAE and laboratory abnormalities 
until study intervention no longer has a clinical effect or can no longer be detected 
systemically (at least 2 days). 
6.8. 
Concomitant Therapy 
Any medication or vaccine, including OTC or prescription medicines, vitamins, and/or herbal 
supplements, that the participant is receiving at the time of enrollment or receives during the 
study must be recorded along with 
● reason for use 
● dates of administration including start and end dates, and 
● dosage information including dose and frequency for concomitant therapy of 
special interest. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
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Participants on the following medications according to local practice must be on a stable regimen 
for at least 4 weeks prior to screening and expected to remain on a stable regimen through the 
end of the Treatment and Assessment Period, unless changes need to be made because of AEs: 
 lipid-lowering drugs (such as statins, ezetimibe, PCSK9 inhibitors, prescription-dose 
niacin, fibrates, fish oil, or other products containing omega-3 fatty acids, including OTC 
preparations), and 
 testosterone, estrogens, progesterone, growth hormone, or progestins. 
 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
7.1. 
Discontinuation of Study Intervention 
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits, as 
shown in the SoA.  
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons 
 if the investigator determines that a systemic hypersensitivity reaction has occurred 
related to study intervention administration, the participant may be permanently 
discontinued from the study intervention, and the sponsor’s designated medical monitor 
should be notified. If the investigator is uncertain about whether a systemic 
hypersensitivity reaction has occurred and whether discontinuation of study intervention 
is warranted, the investigator may consult the sponsor 
 the participant has an AE or an SAE or a clinically significant change in a laboratory 
value that, in the opinion of the investigator, merits discontinuation of study intervention 
and appropriate measures being taken 
 if the participant experiences a hepatic event or liver test abnormality as specified in the 
liver chemistry stopping criteria (see Section 7.1.1), and 
 HBV or HCV: The participant tests positive for HBV DNA (see Section 8.2.4) or tests 
positive for HCV RNA (Section 8.2.5). 
Note: The HBV DNA result is to be confirmed if initial positive test result is positive 
but below the level of quantification. Prior to discontinuation of any 
immunomodulatory and/or immunosuppressive therapy, including study intervention, 
the participant is to be referred to, evaluated, and managed by a specialist physician 
with expertise in evaluation and management of viral hepatitis. The timing of 
discontinuation from study intervention relative to the initiation of any antiviral 
treatment for hepatitis is to be based on the recommendation of the consulting 
specialist physician, in conjunction with the investigator, and aligned with medical 
guidelines and standard of care. 
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7.1.1. 
Liver Chemistry Stopping Criteria 
Interrupting study drug based on liver test elevations in participants with normal or near-
normal baseline liver tests 
In study participants with normal or near-normal baseline liver tests (ALT, AST, alkaline 
phosphatase [ALP] <1.5x ULN), the study drug should be interrupted or discontinued and close 
hepatic monitoring initiated (see Appendix 10.6) if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL >2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
and other consensus guidelines, with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
FDA = Food and Drug Administration; INR = international normalized ratio; TBL = total bilirubin; ULN= upper 
limit of normal. 
 
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Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT, AST, ALP ≥1.5x ULN), the study 
drug should be interrupted or discontinued if one or more of these conditions occur:  
Elevation 
Exception 
ALT or AST >4x baseline 
 
ALT or AST >3x baseline for more than 2 weeks 
 
ALT or AST >2x baseline and either TBL >2x ULN or INR 
>1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >2x baseline with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
 
ALP >2.5x baseline, when the source of increased ALP is the 
liver 
 
ALP >2x baseline and TBL >2x ULN  
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
and other consensus guidelines, with minor modifications 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
FDA = Food and Drug Administration; INR = international normalized ratio; TBL = total bilirubin; ULN= upper 
limit of normal. 
Resuming study drug after elevated liver tests 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited nondrug 
etiology is identified. Otherwise, the study drug should be discontinued. 
7.1.2. 
QTc Stopping Criteria 
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula (QTcF) after enrollment, the investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the electrocardiogram (ECG) printed at the 
time of collection must be documented. Any new clinically relevant finding should be reported 
as an AE.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Discontinuation is expected to be uncommon. 
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A participant may withdraw from the study: 
● at any time at the participant’s own request 
● at the request of the participant’s designee (for example, parents or legal 
guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation (ED) visit, as shown in the SoA. If the participant has not already 
discontinued the study intervention, the participant will be permanently discontinued from the 
study intervention at the time of the decision to discontinue the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up 
A participant 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. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.  
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get investigational product. Public sources may be searched for vital status 
information. If vital status is determined to be deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information. 
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8. 
Study Assessments and Procedures 
● Study procedures and their timing are summarized in the SoA.  
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
8.1. 
Efficacy Assessments 
See Section 9.3 for definitions of the efficacy endpoints. 
8.1.1. 
Primary Efficacy Assessment 
Elevated Lp(a) is recognized as an important risk factor for cardiovascular disease. Lp(a) will be 
collected for each participant at the times shown in the SoA (Section 1.3). 
8.1.2. 
Secondary Efficacy Assessments 
The 2018 AHA/ACC Guideline on the management of blood cholesterol identified Lp(a) 
≥50 mg/dL (≥125 nmol/L) as risk enhancing. As a responder analysis, the proportions of 
participants achieving Lp(a) <125 and <75 nmol/L will be assessed. 
At times specified in the SoA, blood samples will be collected to measure changes in levels of 
these markers 
 ApoB 
 high-sensitivity C-reactive protein (hsCRP) 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Electrocardiograms 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures pulse rate, QRS, QT, and QTc 
intervals. Refer to Section 7.1.2 for QTc withdrawal criteria and any additional QTc readings 
that may be necessary. 
8.2.2. 
Clinical Safety Laboratory Tests 
● See Appendix 10.2 for the list of clinical laboratory tests to be performed and the 
SoA for the timing and frequency. 
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● The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
● All laboratory tests with values considered clinically significantly abnormal 
during participation in the study and deemed to be related to LY3819469, in the 
opinion of the investigator, or within 6 months after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are 
no longer considered clinically significant by the investigator or medical monitor. 
○ If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the SoA, standard 
collection requirements, and laboratory manual. 
● If laboratory values from non-protocol-specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the investigator 
(for example, SAE or AE or dose modification), then report the information as an 
AE.  
8.2.3. 
Hepatic Safety 
Close hepatic monitoring 
Laboratory tests (Appendix 10.6), including ALT, AST, ALP, total bilirubin (TBL), direct 
bilirubin (D. Bil), gamma-glutamyl transferase (GGT), and creatine kinase (CK), should be 
repeated within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or 
decreasing, if one or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s 
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN= upper limit of normal. 
 
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If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including OTC), herbal and dietary supplements, history of alcohol drinking and 
other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for patients with Gilbert’s syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN= upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time, international normalized ratio 
(PT-INR); tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an 
abdominal imaging study (for example, ultrasound or computerized tomography [CT] scan).  
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus 
(HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), acetaminophen levels, 
acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, blood alcohol levels, 
urinary ethyl glucuronide, and blood phosphatidylethanol. Based on the circumstances and the 
investigator’s assessment of the participant’s clinical condition, the investigator should consider 
referring the participant for a hepatologist or gastroenterologist consultation, magnetic resonance 
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cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), 
cardiac echocardiogram, or a liver biopsy.  
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
➢ In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests 
2. Elevated TBL to ≥ 2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
➢ In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
➢ In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event  
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.4. 
Hepatitis B Testing and Monitoring 
As specified in the SoA (Section 1.3), initial testing for HBV infection includes HbsAg and 
hepatitis B core antibody (HbcAb). 
● If HbsAg is positive, the participant is excluded. 
● If HbsAg is negative and HbcAb is negative, the participant is not excluded. 
● If HbsAg is negative and HbcAb is positive, further testing for HBV DNA is 
required. 
○ If the screening HBV DNA is positive, the participant is excluded. 
○ If the screening HBV DNA is negative, the participant is not excluded. Repeat 
testing for HBV DNA is required at least every 3 months during the study. 
Management of enrolled participants with detectable HBV DNA during the study 
If HBV DNA is detected, study intervention will be temporarily withheld or permanently 
discontinued, as described in Section 7.1, and the participant should receive appropriate follow-
up medical care. 
8.2.5. 
Hepatitis C Testing 
As specified in the SoA (Section 1.3), initial testing for HCV infection includes testing for 
anti-HCV. 
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● If anti-HCV is positive, a test for circulating HCV RNA is required. 
● If HCV RNA test is negative, the participant is not excluded. 
● If HCV RNA test is positive, the participant is excluded. 
Participants who have had HCV infection and have been successfully treated, defined as a 
sustained virologic response (HCV RNA by PCR negative for at least 24 weeks following 
treatment completion), are not excluded on the basis of HCV as long as HCV RNA test is 
negative at screening. 
If HCV RNA is detected during the study, the study intervention will be discontinued 
(Section 7.1), and the participant should receive appropriate follow-up medical care. 
8.2.6. 
Injection Site Reactions 
Symptoms and signs of a local injection site reaction (ISR) may include erythema, induration, 
pain, pruritus, and edema.  
If an ISR is reported by a participant or site staff, the ISR CRF will be used to capture additional 
information about this reaction (for example, injection-site pain, degree and area of erythema, 
induration, pruritis and edema). 
8.2.7. 
Hypersensitivity Reactions 
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Appendix 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory.  
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs 
 Product complaints (PCs) 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or study (see Section 7). 
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Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For PCs, 
the investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality. Further information on 
follow-up procedures is provided in Appendix 10.3.  
8.3.1. 
Timing and Mechanism for Collecting Events 
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
AE – related to 
prescreening 
study procedure 
Signing of 
the 
prescreening 
ICF 
Signing of 
the ICF 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE CRF 
SAE paper 
form 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
SAEa – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
Participation 
in study has 
ended 
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of 
study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of 
study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed PC form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC, if 
investigator 
becomes aware 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = serious adverse event. 
a SAEs should not be reported unless the investigator deems them to be possibly related to study treatment or study 
participation. 
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8.3.2. 
Pregnancy 
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator will 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 
24 hours of learning of a participant’s pregnancy.  
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of gestational age, fetal 
status (presence or absence of anomalies) or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
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● Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study, follow the standard discontinuation process and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation. 
8.3.3. 
Major Adverse Cardiovascular Events 
Nonfatal cardiovascular AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise. This committee will be blinded to treatment assignment. 
The nonfatal cardiovascular AEs to be adjudicated include 
 myocardial infarction 
 hospitalization for unstable angina 
 hospitalization for heart failure 
 coronary interventions, such as coronary artery bypass graft or percutaneous coronary 
intervention, and 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack. 
8.4. 
Pharmacokinetics 
 At the visits and times specified in the SoA (Section 1.3), blood samples will be collected 
to determine the LY3819469 plasma concentrations. 
 Participants may need to return to the clinical site for PK-specific visits to provide 
postdose PK samples dependent on the time window of PK sampling. 
 Instructions for the collection and handling of blood samples will be provided by the 
sponsor. Sampling times for PK evaluation are provided as a guidance and should be 
adhered to as closely as possible. The actual date and time (24-hour clock time) of each 
sample collection will be recorded. 
 Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel. 
 A validated assay will be used to determine plasma LY3819469 concentrations from the 
blood samples collected. The blood samples will be analyzed at a laboratory approved by 
the sponsor. The samples will be retained for a maximum of 1 year following last study 
visit for the study. During this time, any samples remaining after the bioanalysis is 
complete may be used for exploratory analyses, such as metabolism, protein binding, or 
bioanalytical method development or validation work. 
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8.5. 
Pharmacodynamics 
Samples to evaluate the PD properties of LY3819469 are included in the efficacy measures and 
not applicable here. 
8.6. 
Genetics 
An optional blood sample for DNA isolation will be collected from participants. 
See Appendix 10.5 for information regarding genetic research and Appendix 10.1.12 for details 
about sample retention and custody. 
8.7. 
Biomarkers 
Serum and plasma samples will be collected and used for exploratory biomarker research, where 
local regulations allow. See Clinical Laboratory Tests and the SoA for sample collection 
information. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3819469, pathways associated with lipid metabolism, mechanism of action of LY3819469, 
and/or research method, or for validating diagnostic tools or assay(s) related to lipid metabolism 
or other relevant disease states. 
Samples may be used for research to develop methods, assays, prognostics, and/or companion 
diagnostics related to the intervention target, disease state, pathways associated with disease, 
and/or the mechanism of action of the study intervention. 
Sample retention is described in Section 10.1.12. 
8.8. 
Immunogenicity Assessments 
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
(if local regulations and ethical review boards allow) and stored for potential future analysis to 
determine antibody production against LY3819469. Antibodies may be further characterized for 
their ability to neutralize the activity of LY3819469. To interpret the results of immunogenicity, 
a venous blood sample will be collected at the same time points to determine the plasma 
concentrations of LY3819469. Samples for immunogenicity should be taken predose when 
applicable and possible. 
In the event of drug hypersensitivity reactions (immediate or nonimmediate), additional samples 
will be collected as described in Section 10.2.1. 
Samples will be retained for a maximum of 15 years after the last participant visit per Section 
10.1.12, or for a shorter period if local regulations and ethical review boards allow, at a facility 
selected by the sponsor. The duration allows the sponsor to respond to future regulatory requests 
related to the LY3819469. Any samples remaining after 15 years will be destroyed. 
8.9. 
Health Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The study hypothesis for the primary objective is that SC injection of LY3819469 16 mg, 96 mg, 
or 400 mg is superior to placebo in percent change from baseline in time-averaged Lp(a) over 
Days 60-180 in participants with elevated Lp(a). 
9.1.1. 
Multiplicity Adjustment 
Treatment comparisons will be performed for the primary objective at the full significance level 
of 0.05. No multiplicity adjustments will be made for the analysis of secondary and exploratory 
objectives. 
9.2. 
Analyses Sets 
This table defines the analysis population and datasets for the purposes of analysis. 
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
All participants who are randomly assigned to a treatment arm. 
Full Analysis Set (FAS) 
All data for patients who are randomized, take at least one dose of study 
medication, and are not discontinued due to inadvertent enrollment. 
Participants will be analyzed according to the treatment they were assigned. 
Abbreviation: ICF = informed consent form. 
9.3. 
Statistical Analyses 
9.3.1. General Considerations 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) or the clinical study report (CSR). Additional exploratory 
analyses of the data will be conducted as deemed appropriate. 
Unless otherwise noted, all tests will be conducted at a 2-sided alpha level of 0.05, and 
confidence intervals will be calculated at 95%, 2-sided. 
Baseline is defined as the last non-missing measurement recorded on or before the randomization 
visit, prior to first dose of intervention, unless otherwise specified. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis 
The primary efficacy assessment, guided by the “treatment-regimen” estimand, which represents 
the efficacy regardless of treatment discontinuation, will be conducted using the Full Analysis 
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Set (FAS). The missing values for Lp(a) measurements at each time point (up to 6 months) will 
be handled by multiple imputation under the assumption of missing at random (MAR). Then, the 
time-averaged Lp(a) for each patient will be calculated based on the observed and imputed data. 
Specifically, the AUC for log-transformed Lp(a) over Day 60 to Day 180 will be calculated 
using the trapezoidal rule according to the scheduled time, and the time-averaged log[Lp(a)] is 
the AUC for log[Lp(a)] divided by 120 (days). The time-averaged Lp(a) is calculated as the 
exponentiation of the time-averaged log[Lp(a)]. 
The change in the time-averaged log[Lp(a)] from baseline will be analyzed using an analysis of 
covariance (ANCOVA) model including treatment, high risk of cardiovascular event (yes/no), 
and baseline log[Lp(a)] as a covariate. For the primary analysis up to Day 180, the two 
LY3819469 treatment groups assigned to 400 mg will be pooled into one treatment group, 
because participants are receiving the same study intervention in the first 180 days. The percent 
change for the time-averaged Lp(a) will be calculated and reported by exponentiating the 
estimates for the change in the time-averaged log[Lp(a)] in the above model and the 
corresponding standard error will be calculated using the delta-method.  
Additional covariates may be added, and this analysis will be detailed in the SAP. 
9.3.3. 
Secondary Endpoint(s)/Estimand(s) Analysis 
Secondary endpoints are listed in Section 3. 
The efficacy analyses for the secondary endpoints will use the FAS described in Section 
9.3.1.and may also pool the two LY3819469 400-mg treatment groups, where appropriate. 
Analyses for percent change from baseline in time-averaged Lp(a) over Days 240-360 will be 
conducted in a manner similar to the primary efficacy analysis discussed in Section 9.3.2.  
The continuous clinical measures, including Lp(a), ApoB, and hsCRP, may be log transformed 
before statistical analyses, if deemed necessary. Analyses for change from baseline in each log-
transformed parameter at Days 60, 180, 240, 360, and 540 will be conducted using mixed model 
for repeated measures (MMRM). The percent change from baseline will be calculated and 
reported by exponentiating the estimates for the change from baseline in above model. 
Analyses for percentages of participants reaching Lp(a) <125 nmol/L and <75 nmol/L at Day 60, 
180, 240, 360, and 540 will be conducted using logistic regression modeling. 
In these models, additional covariates may be added, if deemed necessary. The details will be 
provided in the SAP. 
9.3.4. 
Exploratory Endpoint(s) Analysis 
Details of analyses for the exploratory objectives will be provided in the SAP. 
9.3.5. 
Safety Analyses 
Safety assessments will be guided by an estimand comparing safety of LY3819469 doses with 
placebo irrespective of adherence to intervention. Thus, safety analyses will be conducted using 
the FAS. Safety assessments may also pool the 2 LY3819469 400-mg treatment groups, where 
appropriate. 
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AEs will be coded from the actual term using the Medical Dictionary for Regulatory Activities 
(MedDRA) and reported with preferred terms and system organ class. Selected notable AEs of 
interest may be reported using high-level terms or Standardized MedDRA Queries. 
Summary statistics will be provided for incidence of 
 treatment-emergent adverse events (TEAEs) 
 SAEs 
 study discontinuation due to AEs 
 intervention discontinuation due to AEs 
 deaths, and 
 other cardiovascular endpoints. 
Counts and proportions of participants experiencing AEs will be reported for each treatment 
group, and Fisher’s exact test will be used to compare the treatment groups. 
9.3.5.1. 
Laboratory Measures, Vital Signs, and Electrocardiograms 
Laboratory measures and vital signs will be summarized for each scheduled visit by 
 actual measures at baseline and postbaseline 
 change from baseline to postbaseline, or 
 percent change from baseline to postbaseline. 
The laboratory measures may be log-transformed before statistical analyses, if deemed 
necessary. Laboratory measures may also pool the 2 LY3819469 400-mg treatment groups, 
where appropriate. Continuous variables, as well as the change from baseline for these variables 
or other appropriate transformed variables, will be analyzed by MMRM models as described in 
Section 9.3.1. 
The percentages of participants with treatment-emergent abnormal, high, or low measures, 
including laboratory and vital parameters, will be summarized and compared between treatment 
groups using Fisher’s exact test. 
The analysis details will be provided in the SAP. 
9.3.6. 
Pharmacokinetic and Pharmacodynamic Analyses 
LY3819469 concentration data will be summarized and analyzed using a population PK 
approach via nonlinear mixed-effects modeling.  
The relationships between LY3819469 dose and concentration and selected efficacy and safety 
endpoints may be characterized. Additionally, the impact of intrinsic and extrinsic factors, such 
as age, weight, gender, and liver function on PK and PD parameters, may be examined as 
needed. 
If anti-drug antibody (ADA) titers are detected from immunogenicity testing, then the impact of 
immunogenicity titers on LY3819469 PK or any relevant efficacy parameters may also be 
examined. Additional analyses may be conducted if they are deemed appropriate. 
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9.3.7. 
Immunogenicity Assessments  
If data from validated immunogenicity assays are available, treatment-emergent anti-drug 
antibodies (TE-ADAs) may be assessed.  
TE-ADAs are defined as participants  
 with a 2-fold (1 dilution) increase in titer than the minimum required dilution if no ADAs 
were detected at baseline (treatment-induced ADA), or  
 with a 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected 
at baseline (treatment-boosted ADA).  
The frequency and percentage of participants with preexisting ADA and who are TE-ADA 
positive (TE-ADA+) to LY3819469 will be tabulated.  
The distribution of titers and frequency of neutralizing antibodies (if assessed) for the TE-ADA+ 
participants may also be tabulated.  
The relationship between the presence of antibodies and PK parameters, efficacy response, or 
safety to LY3819469 may also be assessed. Additional details may be provided in the SAP. 
9.3.8. 
Subgroup Analyses 
Subgroup analyses of important factors, such as baseline Lp(a) level, and other factors to be 
specified in the SAP, are planned for the key outcomes. The models used for these analyses will 
vary depending on the subgroups and the outcome. Other exploratory subgroup analyses may be 
performed as deemed appropriate. Details of the modeling will be provided in the SAP. 
9.4. 
Interim Analysis 
There may be up to 3 interim analyses.   
A planned interim analysis may be conducted when at least 10% of the participants complete 
Day 180 at Visit 7 or discontinue the study. The interim will be for the purpose of internal 
planning and decision-making and may assess safety, PK, and/or efficacy measures. Additional 
details related to statistical methods will be described in the SAP. If this happens, an assessment 
committee (AC) will be formed to review the interim analyses in an unblinded manner. The 
details regarding the number of participants and type of analysis will be provided in the AC 
charter and in the unblinding plan. Information that may unblind the study during the analyses 
will not be reported to study sites or blinded study team members before the study has been 
unblinded. Study sites will receive information about interim results only if deemed necessary 
for the safety of the participants. The study will not be stopped based on the efficacy of 
LY3819469 versus placebo. Therefore, there will be no inflation of the type 1 error rate, and no 
need to employ an alpha spending function or multiplicity adjustment. 
The primary database lock and primary data analysis for Study EZEB may occur when all 
participants have completed Day 180 (Visit 7). After primary analysis, additional efficacy and 
safety assessment may occur when all participants have completed 240 days (Visit 9) and 10% of 
participants have completed 360 days (Visit 11) of the treatment. The final database lock and 
final data analysis will occur when all randomized participants have completed the study. 
Participants and investigators will remain blinded until the completion of the study.  
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The addition of an interim analysis can be determined at any time during the study and will not 
result in a protocol amendment. The SAP will describe the interim analyses in greater detail. 
9.5. 
Sample Size Determination 
Approximately 254 participants will be randomly assigned in a 1:2:2:2:2 ratio to LY3819469 
16 mg 2 doses: 96 mg 2 doses: 400 mg 2 doses: 400 mg 1 dose and placebo 1 dose:placebo 
2 doses. Assuming a 15% dropout rate, this results in approximately 24 completers for the 16-mg 
group and 48 completers per arm for the rest of the groups. 
Assuming a standard deviation of 20%, and a 2-sided alpha level of 0.05, the completers for each 
treatment arm will provide >99% power to detect a treatment difference of 70% reduction for the 
primary endpoint of LY3819469 versus placebo. The sample size was determined appropriate to 
provide a sufficient amount of safety data. 
 
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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
○ Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● 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 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
○ Reporting to the sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
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10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participant and answer all questions 
regarding the study. 
● Participants must be informed that their participation is voluntary. Participants 
will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data 
protection requirements, where applicable, and the IRB/IEC or study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant and is kept on file. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent.  
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
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10.1.5. 
Committees Structure 
10.1.5.1. External Clinical Endpoints Committee 
An independent clinical endpoint committee, external to Lilly, will be formed to adjudicate 
major adverse cardiac events (MACE) and deaths. This committee will be blinded to treatment 
assignment. 
10.1.6. 
Dissemination of Clinical Study Data 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
Data and documents, including the study protocol, SAP, CSR, and blank or annotated case report 
forms, will be provided in a secure data sharing environment for up to 2 years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance 
● All participant data relating to the study will be recorded on printed or electronic 
CRFs unless transmitted to the sponsor or designee electronically (for example, 
laboratory 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. 
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● Quality tolerance limits (QTLs) will be predefined to identify systematic issues 
that can impact participant safety and/or reliability of study results. These 
predefined parameters will be monitored during the study and important 
excursions from the QTLs and remedial actions taken will be summarized in the 
CSR. 
● Monitoring details describing strategy (for example, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities and requirements, 
including handling of noncompliance issues and monitoring techniques, are 
provided in the Monitoring Plan. 
● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations). 
● Study monitors will perform ongoing source data verification to confirm that data 
transcribed into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
Clinical Trial Agreement (CTA) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
● In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
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of the data capture systems. Prior to decommissioning, the investigator will receive or access an 
archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
 
10.1.8. 
Source Documents 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
● Data reported on or entered in the CRF and 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. 
● Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first participant to enter screening. 
Study or Site Termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
● Discontinuation of further study intervention development 
For site termination: 
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● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
● Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy 
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information 
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
10.1.12. 
Sample Retention 
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
LY3819469 or after LY3819469 become(s) commercially available. 
 
Sample Type 
Custodian 
Retention Period After Last 
Participant Visita 
Exploratory Biomarker Samples 
Sponsor or Designee 
7 years 
PK 
Sponsor or Designee 
1 years  
Genetics 
Sponsor or Designee 
7 years 
Immunogenicity 
Sponsor or Designee 
15 years 
Abbreviation: PK = pharmacokinetic. 
a Retention periods may differ locally. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
● The tests detailed in the table below will be performed as noted in the table below. 
● Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. Additionally, if the local 
laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be recorded. 
● In circumstances where the sponsor approves local laboratory testing in lieu of 
central laboratory testing (in the table below), the local laboratory must be 
qualified in accordance with applicable local regulations. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 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. 
● Investigators must document their review of the laboratory safety results. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel. 
Clinical Laboratory Tests  
Comments  
Hematology 
Assayed by Lilly-designated laboratory. 
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration  
  
Absolute neutrophil count (calculation)  
  
Leukocytes (WBCs)  
  
Differential 
  
Percent and/or absolutes count of: 
  
   Neutrophils, segmented 
  
   Bands  
  
   Lymphocytes 
  
   Monocytes 
  
   Eosinophils 
  
   Basophils 
  
Platelets 
  
Cell morphology (RBCs and WBCs) 
  
  
  
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Clinical Laboratory Tests  
Comments  
Clinical Chemistry 
Assayed by Lilly-designated laboratory. 
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
ALP 
  
ALT 
  
AST 
  
GGT 
  
BUN 
  
Creatinine  
  
CK 
  
Uric acid 
  
Total protein 
  
Albumin 
  
Calcium 
  
Phosphorus 
  
Glucose 
  
  
  
Lipid Panel 
Assayed by Lilly-designated laboratory. 
HDL-C 
 
LDL-C 
Generated by Lilly-designated laboratory. 
If triglycerides are >400; direct LDL will be 
measured. 
VLDL-C 
Generated by Lilly-designated laboratory. 
Cholesterol 
 
Triglycerides 
 
  
  
Urinalysis 
Assayed by Lilly-designated laboratory. 
Specific gravity 
  
pH 
  
Protein 
  
Glucose 
  
Ketones 
  
Bilirubin 
  
Urobilinogen 
  
Blood 
  
Nitrite 
  
Urine leukocyte esterase 
  
Microscopic examination of sediment 
  
  
  
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Clinical Laboratory Tests  
Comments  
Hormones (female) 
  
Serum pregnancy  
Assayed by Lilly-designated laboratory.  
FSH  
Assayed by Lilly-designated laboratory.  
  
  
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI)  
  
UACR 
 
  
  
TB, HIV, and Hepatitis Serology 
Assayed by Lilly-designated laboratory. 
HIV testing  
 
HCV testing: 
 
   HCV antibody  
 
   HCV RNA 
 
HBV testing:  
 
   HBV DNA  
Performed only for participants who test positive 
for HbcAb.  
   HbcAb  
  
   HbsAg  
  
   HbsAb 
  
  
  
Pharmacokinetic Samples  
Assayed by Lilly-designated laboratory. 
 
LY3819469 concentration 
Results will not be provided to the investigative 
sites. 
 
 
Immunogenicity (ADA) samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative 
sites. 
Anti-LY3819469 antibodies 
 
 
 
Additional Testing  
Assayed by Lilly-designated laboratory. 
Lp(a) 
Results will be provided to the investigative sites 
during prescreening or screening. Results will not 
be provided to the investigative sites after 
randomization. 
ApoB 
Results will not be provided to the investigative 
sites. 
hsCRP 
Results will be provided to the investigative sites. 
TSH 
HbA1c  
  
  
  
  
Genetics Sample 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative 
sites. 
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Clinical Laboratory Tests  
Comments  
Whole blood (EDTA) 
  
Exploratory Biomarker Storage Samples 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative 
sites. 
  Serum 
  
  Plasma (EDTA) 
  
Abbreviations: ADA = anti-drug antibodies; ALP = alkaline phosphatase; ALT = alanine aminotransferase; 
ApoB = apolipoprotein b; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CK = creatine kinase; 
CKD-EPI = chronic kidney disease epidemiology collaboration; DNA = deoxyribonucleic acid; 
EDTA = ethylenediamine tetraacetic acid; eGFR = estimated glomerular filtration rate; FSH = follicle-
stimulating hormone; GGT = gamma-glutamyl transferase; HbA1c = hemoglobin A1c; HbcAb = hepatitis B core 
antibody; HbsAb = hepatitis B surface antibody; HbsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HDL-C = high-density lipoprotein-cholesterol; HIV = human immunodeficiency virus; 
hsCRP = high-sensitivity C-reactive protein; LDL-C = low-density lipoprotein-cholesterol; 
Lp(a) = Lipoprotein(a); RBC = red blood cell; RNA = ribonucleic acid; TSH = thyroid stimulating hormone; 
UACR = urine albumin creatinine ratio; VLDL-C = very low-density lipoprotein; WBC = white blood cell. 
10.2.1. 
Laboratory Samples to be Obtained at the Time of a Systemic Hypersensitivity 
Event 
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory test results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up predose samples at the next regularly scheduled laboratory sample collection, 
ideally prior to the next dose after the event, to assess post-event return-to-baseline values. 
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Timing 
Preferred Sample 
Typea 
Laboratory Testb 
Collect from 30 minutes to 4 hours 
after the start of the event.  
● Note: The optimal 
collection time is from 1 to 
2 hours after the start of event. 
Serum 
total tryptase 
Serum 
complements (C3, C3a, and C5a)  
Serum 
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine 
panel that includes these 3 cytokines)  
Collect only if not already collected 
on the same day as the event. 
● Note: If collecting, collect 
up to 12 hours after the start of 
the event. 
Serum 
LY3819469 ADA 
Serum/plasma 
LY3819469 concentration 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
a Sample type may be different depending on local requirements. 
b All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE 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 medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention 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. 
 Medication error, misuse, or abuse of investigational medicinal product, including 
signs, symptoms, or clinical sequelae.  
 Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. 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 AE or SAE if they fulfill the definition of an AE or SAE.  
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
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 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) 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 AEs. 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 AE should be 
considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent 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 (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
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f. 
Other situations: 
 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE 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 participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually 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.  
10.3.3. 
Definition of Product Complaints 
Product Complaint 
 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 study intervention. When the ability to use the study intervention 
safely is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator 
to review all documentation (for example, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information 
in the participant’s medical records, in accordance with the investigator’s normal 
clinical practice. AE/SAE information is reported on the appropriate CRF page and 
product complaint information is reported on the Product Complaint Form. 
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Note: An event may meet the definition of both a product complaint and an AE/SAE. 
In such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.  
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.  
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB in their assessment. 
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 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
10.3.5. 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see 
next section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool 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 SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on an SAE paper form (see next 
section) or to the medical monitor/SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in the SAE paper form. 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the SAE paper form.  
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10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
● Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention 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 intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Word/Phrase 
Definition 
Women of childbearing 
potential (WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
 
Women not of 
childbearing potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 have a congenital anomaly such as Müllerian agenesis  
 are infertile due to surgical sterilization, or  
 are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, 
bilateral salpingo-oophorectomy, bilateral salpingectomy, or 
bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman: 
 at any age at least 6 weeks postsurgical bilateral 
oophorectomy with or without hysterectomy, confirmed by 
operative note; or  
 aged at least 40 years and up to 55 years with an intact 
uterus, not on hormone therapya, who has had cessation of 
menses for at least 12 consecutive months without an 
alternative medical cause, AND with a follicle-stimulating 
hormone >40 mIU/mL; or  
 55 years or older not on hormone therapy, who has had at 
least 12 months of spontaneous amenorrhea, or 
 aged at least 55 years with a diagnosis of menopause prior to 
starting hormone replacement therapy. 
 
Abbreviation: SERM = selective estrogen receptor modulator. 
a Women should not be taking medications during amenorrhea such as oral contraceptives, hormones, 
gonadotropin-releasing hormone, anti-estrogens, SERMs, or chemotherapy that could induce transient 
amenorrhea. 
 
10.4.2. 
Contraception Guidance 
10.4.2.1. Female Participants 
Female participants of childbearing potential are excluded from the trial. 
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10.4.2.2. Male Participants 
The table below describes contraception guidance for men. 
Topic 
Guidance 
For all men  
should refrain from sperm donation for the 
duration of the study  
Contraception for men with partners of 
childbearing potential  
 
either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 
must use condoms during intercourse for 
the duration of the study 
Contraception for men in exclusively same sex 
relationships, as their preferred and usual lifestyle 
Are not required to use contraception 
 
Examples of highly effective, effective, and unacceptable methods of contraception can be found below. 
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 
mini-pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women 
<198 pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o  diaphragm with spermicide, or 
o female condom with spermicide 
 
Note: The barrier method must include use of a 
spermicide (i.e., condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone  
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal, 
 
post coital douche 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Genetics 
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, an optional blood sample 
will be collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to study intervention or 
cardiovascular disease and related diseases. They may also be used to develop 
tests or assays including diagnostic tests related to study intervention and 
cardiovascular disease. Genetic research may consist of the analysis of 1 or more 
candidate genes or the analysis of genetic markers throughout the genome or 
analysis of the entire genome (as appropriate). 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to study intervention or study interventions of this 
class to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on study intervention continues but 
no longer than 7 years or other period as per local requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Hepatic Evaluation Testing 
See Section 8.2.4 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing: 
   Hemoglobin 
    HAV total antibody 
   Hematocrit 
    HAV IgM antibody 
   Erythrocytes (RBCs – red blood cells) 
Hepatis B virus (HBV) testing: 
   Leukocytes (WBCs – white blood cells) 
    Hepatitis B surface antigen (HbsAg) 
   Differential: 
    Hepatitis B surface antibody (anti-HBs) 
       Neutrophils, segmented 
    Hepatitis B core total antibody (anti-HBc) 
       Lymphocytes 
    Hepatitis B core IgM antibody 
       Monocytes 
    HBV DNA b 
       Basophils 
Hepatis C virus (HCV) testing: 
       Eosinophils 
    HCV antibody 
   Platelets 
    HCV RNAb 
   Cell morphology (RBC and WBC) 
Hepatitis D virus (HDV) testing: 
Hepatic Clinical Chemistry Panel 
    HDV antibody 
   Total bilirubin 
Hepatitis E virus (HEV) testing: 
   Direct bilirubin 
    HEV IgG antibody 
   Alkaline phosphatase (ALP) 
    HEV IgM antibody 
   Alanine aminotransferase (ALT) 
    HEV RNA b 
   Aspartate aminotransferase (AST) 
Anti-nuclear antibody (ANA) 
   Gamma-glutamyl transferase (GGT) 
Anti-smooth muscle antibody (ASMA) a 
   Creatine kinase (CK) 
Anti-actin antibody c 
Hepatic Coagulation Panel 
Immunoglobulin IgA (quantitative) 
   Prothrombin time, INR (PT-INR) 
Immunoglobulin IgG (quantitative) 
Urine Chemistry 
Immunoglobulin IgM (quantitative) 
   Drug screen 
Epstein-Barr virus (EBV) testing: 
Haptoglobin 
    EBV antibody 
Tests assayed ONLY by investigator-designated local laboratory  
Acetaminophen 
Cytomegalovirus (CMV) testing: 
Acetaminophen protein adducts 
    CMV antibody 
Alkaline phosphatase isoenzymes 
    CMV DNA b 
Ceruloplasmin 
Herpes simplex virus (HSV) testing: 
Copper 
    HSV (Type 1 and 2) antibody 
Ethyl alcohol (EtOH) 
    HSV (Type 1 and 2) DNA b 
Phosphatidylethanol (Peth) 
Liver kidney microsomal type 1 (LKM-1) antibody 
Urine Chemistry 
Microbiology  
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Tests assayed ONLY by investigator-designated local laboratory  
    Ethyl glucuronide (EtG) 
Culture: 
Epstein-Barr virus (EBV) testing: 
    Blood 
    EBV DNAb 
    Urine 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
 
 
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10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be used only 
during specific time periods as directed by the sponsor in partnership with the investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may implement 
changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which notification is 
required, for example, upon implementation and suspension of changes. All approvals and notifications 
must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. Additional 
important considerations for making a change are compliance with GCP, enabling participants to continue 
safely in the study, and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 
participation in remote visits, as defined in Section “Remote Visits” 
 
dispensation of additional study intervention during an extended treatment period 
 
alternate delivery of study intervention and ancillary supplies, and 
 
provision of their personal or medical information required prior to implementation of these 
activities. 
 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
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Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but are 
not limited to 
 
AE review 
 
concomitant medication review 
 
substance use (alcohol), and 
 
PCs (if applicable). 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor. Procedures performed at such visits 
include, but are not limited to 
 
concomitant medications 
 
collection of blood samples 
 
physical assessments, and 
 
health information. 
Other alternative locations: A local laboratory may be used for laboratory draws. 
Assessments that may need to be delayed until the next on-site visit or missed, depending on the 
length of time that sites or participants are impacted and depending on when on-site visits are 
due, include 
 
vital signs 
 
weight 
 
symptom-directed physical examination, and 
 
laboratory tests if a local laboratory cannot be used. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the reporting of 
AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as reasonably 
possible, while ensuring the safety of both the participants and the site staff. 
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Local laboratory testing option 
Local laboratory testing may be conducted in lieu of Lilly-designated laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
Lilly-designated laboratory testing must be retained for PK, Lp(a), ApoB, hsCRP, and the lipid panel. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site visits, the 
site should work with the sponsor to determine appropriate actions. These actions may include 
 
asking the participant to go to the site and receive study supplies from site staff without 
completion of a full study visit 
 
asking the participant’s designee to go to the site and receive study supplies on a participant’s 
behalf 
 
arranging delivery of study supplies, and 
 
working with the sponsor to determine how study intervention that is typically administered 
on site will be administered to the participant; for example, during a mobile healthcare visit 
or at an alternate location such as an infusion center. 
 
These requirements must be met before action is taken: 
 
Alternate delivery of study intervention should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity. The existing protocol 
requirements for product accountability remain unchanged, including verification of 
participant’s receipt of study supplies. 
 
When delivering supplies to a location other than the study site (for example, participant’s 
home), the investigator, sponsor, or both should ensure oversight of the shipping process to 
ensure accountability and product quality, that is, storage conditions maintained and intact 
packaging upon receipt. 
 
Instructions may be provided to the participant or designee on the final disposition of any 
unused or completed study supplies. 
If study intervention will be administered to the participant during a mobile healthcare visit or at an 
alternate location, these additional requirements must be met: 
 
Only authorized study personnel may supply, prepare, or administer study intervention. 
 
Follow all other requirements that are consistent with the main protocol.  
 
Screening period guidance 
To ensure safety of study participants, laboratory values, and other eligibility assessments taken at 
prescreening and screening visits are valid for a maximum of 60 days. The following rules will be applied 
for active, nonrandomized participants whose participation in the study must be paused due to exceptional 
circumstances: 
 
If screening is paused for less than 60 days from signing the ICF to randomization visit: the 
participant will proceed to the next study visit per the usual SoA, provided that randomization 
visit must be conducted within 45 days from the screening visit. 
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o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted participant’s 
consent and document this confirmation in the source documentation. 
 
If screening is paused for more than 60 days from screening visits to randomization visit: the 
participant must be discontinued because of screening interruption due to an exceptional 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. This rescreen is in addition to the one 
allowed by the main protocol. The screening procedures per the usual SoA should be 
followed, starting at screening visit to ensure participant eligibility by randomization visit. 
 
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants should 
complete the usual SoA. To maximize the possibility that these visits can be conducted as on-site visits, 
the windows for visits may be adjusted, upon further guidance from the sponsor. This minimizes missing 
data and preserves the intended conduct of the study. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits type, and conducted activities were 
affected by exceptional circumstances. Dispensing or shipment records of study intervention and relevant 
communications, including delegation, should be filed with site study records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely manner. 
 
 
 
 
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10.8. 
Appendix 8: Abbreviations and Definitions 
Term 
Definition 
AC 
assessment committee 
ACC 
American College of Cardiology 
ADA 
anti-drug antibodies 
AE 
adverse event 
AHA 
American Heart Association 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Apo(a) 
apolipoprotein(a) 
ApoB 
apolipoprotein B 
ASCVD 
atherosclerotic cardiovascular disease 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
blinding/masking 
A double-blind study is one in which neither the participant nor any of the investigators or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received. 
CAD 
coronary artery disease 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMV 
cytomegalovirus 
Companion 
diagnostic  
An in vitro diagnostic device (assay or test) that provides information that is essential for 
the safe and effective use of a corresponding therapeutic product. 
Complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
Compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
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CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CSR 
clinical study report 
CT 
computerized tomography 
CTA 
Clinical Trial Agreement 
D. Bil 
direct bilirubin 
DNA 
deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
ED 
early discontinuation 
EDC 
electronic data capture system 
eGFR 
estimated glomerular filtration rate 
Enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the study 
are those who have been assigned to a treatment. 
Enter 
Participants entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERCP 
endoscopic retrograde cholangiopancreatography 
EU 
European Union 
FAS 
Full Analysis Set 
GCP 
good clinical practice 
GGT 
gamma-glutamyltransferase 
HbA1c 
hemoglobin A1c 
HBV 
hepatitis B virus 
HbcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HDV 
hepatitis D virus 
HIV 
human immunodeficiency virus 
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hsCRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
Informed consent 
A process by which a participant voluntarily confirms their willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the participant’s decision to participate. Informed consent is documented by means of a 
written, signed, and dated informed consent form. 
Interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created or locked. 
INR 
international normalized ratio 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to gain 
further information about the authorized form. 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IWRS 
interactive web-response system 
Lp(a) 
lipoprotein(a) 
MACE 
major adverse cardiac events 
MedDRA 
Medical Dictionary for Regulatory Activities 
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medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication errors generally involve a failure to uphold one or 
more of the five “rights” of medication use: the right participant, the right drug, the 
right dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
Misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MMRM 
mixed model for repeated measures 
MRCP 
magnetic resonance cholangiopancreatography 
OTC 
over the counter 
participant 
equivalent to CDISC term “subject”: an individual who participates in a clinical trial, either 
as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PCR 
polymerase chain reaction 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PT-INR 
prothrombin time-INR 
QTc 
corrected QT interval 
QTcF 
QT interval corrected using Fridericia’s formula 
QTL 
quality tolerance limit 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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SC 
subcutaneous 
screen 
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
siRNA 
small interfering ribonucleic acid 
SNP 
single-nucleotide polymorphism 
SoA 
Schedule of Activities 
TBL 
total bilirubin 
TE-ADA 
treatment-emergent anti-drug antibodies 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment. 
ULN 
upper limit of normal 
WNOCBP 
women not of childbearing potential 
WOCBP 
women of childbearing potential 
 
 
 
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