Conditions: Dyslipidemias Lipid Metabolism Disorders Metabolic Diseases Hyperlipoproteinemia
Keywords: Triglycerides LDL Cholesterol Mixed Dyslipidemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 205
Healthy volunteers: no

Brief summary:
This a multicenter, Phase 2b, double-blind, placebo-controlled, parallel group study to provide data on efficacy and safety of LY3561774 administered subcutaneously at various doses in participants with mixed dyslipidemia and on a stable dose of a statin.

Detailed description:

Arms:
arm 1: Participants received 100 milligram (mg) LY3561774 subcutaneously (SC) on Day 0 and Day 90 (-5 to +10 days). Follow up was continued until Day 360. arm 2: Participants received 400 mg LY3561774 SC on Day 0 and Day 90 (-5 to +10 days). Follow up was continued until Day 360. arm 3: Participants received 800 mg LY3561774 SC on Day 0 and Day 90 (-5 to +10 days). Follow up was continued until Day 360. arm 4: Participants received placebo SC on Day 0 and Day 90 (-5 to +10 days). Follow up was continued until Day 360.

Interventions: intervention 1: LY3561774 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_000.pdf: 
Protocol J3F-MC-EZCB (e)
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate 
the Efficacy and Safety of LY3561774 in Adults With Mixed Dyslipidemia 
NCT05256654 
Approval date: 14-Feb-2023 


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
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 LY3561774, 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 LY3561774 in Adults with Mixed Dyslipidemia 
Protocol Number: J3F-MC-EZCB 
Amendment Number: e 
Compound: LY3561774 
Brief Title: 
Efficacy and Safety of LY3561774 Compared with Placebo in Adults with Mixed Dyslipidemia 
Study Phase: 2 
Acronym: PROLONG-ANG3 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers 
IND: 147340 
EudraCT: 2021-005407-13 
Document ID: VV-CLIN-077581 
Approval Date: Protocol amendment (e) Electronically Signed and Approved by Lilly on date 
provided below. 
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
2 
Medical Monitor Name and Contact Information will be provided separately. 
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
3 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Amendment (d) 
24-Aug-2022
Amendment (c) 
03-Aug-2022
Amendment (b) 
09-May-2022
Amendment (a) 
08-Dec-2021
Original Protocol 
18-Nov-2021
Amendment [e] 
This amendment is considered to be substantial. 
Overall Rationale for the Amendment: 
The rationale for the amendment is to modify some of the inclusion and exclusion criteria to 
include a broader population who may benefit from the therapy, as well as to incorporate other 
minor changes.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1. Synopsis 
Added the safety-related secondary objective 
and endpoints 
Modified to state that the dosing will occur 
twice on Day 0 and Day 90 (-5 to +10 days) 
Changes to study design and for 
clarification 
Section 1.3. Schedule of 
Activities (SoA) 
Changed the visit tolerance interval from ±5 
to “-5 to +10” for Visit 6 
Changed the follow-up visit V801 to on-site 
for all sites including the US 
Clarified that the second PK sample will be 
taken 4-12 hr post-dose (minimum 2 hr) 
To give more flexibility to 
participants with COVID 
infection 
Since ECG is required at V801, 
an on-site ECG is preferable 
Clarified the timing of the second 
PK sample 
Section 3 Objectives, 
Endpoints, and Estimands 
Added the safety-related secondary objective 
and endpoint 
For intercurrent events, added language to 
indicate that the excluded medications or 
new initiation of any lipid-lowering drugs are 
handled by hypothetical strategies 
Added safety objective to align 
with trial title 
Clarification for the estimand 
Section 4.1. Overall Design 
Modified dosing at Day 90 (-5 to +10 days) 
To give more flexibility to 
participants with COVID 
infection 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
4 
Section 5.1 Inclusion 
Criteria 
Modified age limit from 40 to 18 years of age 
for IC #1 
Modified the lower limit of fasting TG to 150 
mg/dL (1.69 mmol/L) for IC #2 
Modified the cut-off for fasting LDL-C to 70 
mg/dL (1.81 mmol/L) for IC #3 
Added non-HDL-C >130 mg/dL (3.36 
mmol/L) as IC #51 
To include a broader population 
that could benefit from this 
therapy 
Section 5.2. Exclusion 
Criteria 
Modified EC #31 so that anemia will need to 
be clinically relevant at the discretion of the 
investigator for the participant to be excluded 
 
Deleted the word “supine” from EC #34 
To limit exclusion only to 
clinically relevant anemia. 
 
For consistency with protocol 
Section 8.2.2 
Section 6.1. Study 
Intervention(s) Administered 
Modified to state that each injection should 
be delivered into separate quadrants when 
multiple injections are needed 
To provide general advice in case 
of multiple injections 
Section 10.2.1. Laboratory 
Samples Obtained at the 
Time of as Systemic 
Hypersensitivity Event 
Only plasma samples will be collected to test 
the LY3561774 concentrations 
Correction of the sample type 
Throughout the document 
Minor editorial and format changes 
For clarity 
 
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
5 
Table of Contents  
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ..........................................................................................12 
2. 
Introduction ...................................................................................................................20 
2.1. 
Study Rationale ...............................................................................................................20 
2.2. 
Background .....................................................................................................................20 
2.3. 
Benefit/Risk Assessment ................................................................................................22 
2.3.1. 
Risk Assessment .............................................................................................................22 
2.3.2. 
Benefit Assessment .........................................................................................................22 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................22 
3. 
Objectives, Endpoints, and Estimands .......................................................................23 
4. 
Study Design ..................................................................................................................26 
4.1. 
Overall Design ................................................................................................................26 
4.1.1. 
Design Outline ................................................................................................................26 
4.2. 
Scientific Rationale for Study Design ............................................................................27 
4.3. 
Justification for Dose ......................................................................................................27 
4.4. 
End of Study Definition ..................................................................................................28 
5. 
Study Population ...........................................................................................................29 
5.1. 
Inclusion Criteria ............................................................................................................29 
5.2. 
Exclusion Criteria ...........................................................................................................30 
5.3. 
Lifestyle Considerations .................................................................................................32 
5.4. 
Screen Failures ................................................................................................................32 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................33 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................34 
6.1. 
Study Intervention(s) Administered................................................................................34 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................34 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................35 
6.4. 
Study Intervention Compliance ......................................................................................36 
6.5. 
Dose Modification ..........................................................................................................36 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................36 
6.7. 
Treatment of Overdose ...................................................................................................36 
6.8. 
Concomitant Therapy .....................................................................................................36 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................38 
7.1. 
Discontinuation of Study Intervention ............................................................................38 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................38 
7.1.2. 
QTc Stopping Criteria .....................................................................................................39 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................39 
7.3. 
Lost to Follow up ............................................................................................................40 
8. 
Study Assessments and Procedures.............................................................................41 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
6 
8.1. 
Efficacy Assessments .....................................................................................................41 
8.1.1. 
Primary Efficacy Assessment .........................................................................................41 
8.1.2. 
Secondary Efficacy Assessments ....................................................................................41 
8.2. 
Safety Assessments .........................................................................................................41 
8.2.1. 
Physical Examinations ....................................................................................................41 
8.2.2. 
Vital Signs .......................................................................................................................42 
8.2.3. 
Electrocardiograms .........................................................................................................42 
8.2.4. 
Magnetic Resonance Imaging .........................................................................................42 
8.2.5. 
Clinical Safety Laboratory Tests ....................................................................................43 
8.2.6. 
Hepatic Monitoring .........................................................................................................43 
8.2.7. 
Pregnancy Testing ...........................................................................................................46 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................46 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................47 
8.3.2. 
Pregnancy ........................................................................................................................49 
8.3.3. 
Hypersensitivity Reactions .............................................................................................50 
8.3.4. 
Injection-Site Reactions ..................................................................................................50 
8.3.5. 
Major Adverse Cardiovascular Events (MACE) ............................................................50 
8.4. 
Pharmacokinetics ............................................................................................................50 
8.4.1. 
Bioanalytical ...................................................................................................................51 
8.5. 
Pharmacodynamics .........................................................................................................51 
8.6. 
Genetics ..........................................................................................................................51 
8.7. 
Biomarkers ......................................................................................................................51 
8.8. 
Immunogenicity Assessments.........................................................................................52 
8.9. 
Health Economics ...........................................................................................................52 
9. 
Statistical Considerations .............................................................................................53 
9.1. 
Statistical Hypotheses .....................................................................................................53 
9.2. 
Analyses Sets ..................................................................................................................53 
9.3. 
Statistical Analyses .........................................................................................................53 
9.3.1. 
General Considerations ...................................................................................................53 
9.3.2. 
Primary Endpoint/Estimand Analysis .............................................................................54 
9.3.3. 
Secondary Endpoint(s) Analysis .....................................................................................55 
9.3.4. 
Tertiary/Exploratory Analysis ........................................................................................55 
9.3.5. 
Safety Analyses ...............................................................................................................55 
9.3.6. 
Pharmacokinetic and Pharmacodynamic Analyses ........................................................56 
9.3.7. 
Immunogenicity Assessments .........................................................................................56 
9.3.8. 
Subgroup Analyses .........................................................................................................57 
9.4. 
Interim Analysis ..............................................................................................................57 
9.5. 
Sample Size Determination ............................................................................................58 
10. 
Supporting Documentation and Operational Considerations ..................................59 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................59 
10.1.1. Regulatory and Ethical Considerations ...........................................................................59 
10.1.2. Financial Disclosure........................................................................................................59 
10.1.3. Informed Consent Process ..............................................................................................60 
10.1.4. Data Protection................................................................................................................60 
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Protocol J3F-MC-EZCB(e) 
7 
10.1.5. Committees Structure......................................................................................................60 
10.1.6. Dissemination of Clinical Study Data.............................................................................61 
10.1.7. Data Quality Assurance ..................................................................................................61 
10.1.8. Source Documents ..........................................................................................................63 
10.1.9. Study and Site Start and Closure ....................................................................................63 
10.1.10. Publication Policy ...........................................................................................................64 
10.1.11. Investigator Information .................................................................................................64 
10.1.12. Sample Retention ............................................................................................................64 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................65 
10.2.1. Laboratory Samples Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................69 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................70 
10.3.1. Definition of AE .............................................................................................................70 
10.3.2. Definition of SAE ...........................................................................................................71 
10.3.3. Definition of Product Complaints ...................................................................................72 
10.3.4. Recording and Follow-up of AE and/or SAE and Product 
Complaints ......................................................................................................................73 
10.3.5. Reporting of SAEs ..........................................................................................................74 
10.3.6. Regulatory Reporting Requirements ...............................................................................75 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................76 
10.4.1. Definitions.......................................................................................................................76 
10.4.2. Contraception Guidance..................................................................................................77 
10.5. 
Appendix 5: Genetics......................................................................................................79 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................80 
10.7. 
Appendix 7: Concomitant Medication Information........................................................82 
10.7.1. ACC/AHA Statin Therapy List .......................................................................................82 
10.7.2. Permitted Concomitant Medications ...............................................................................82 
10.7.3. Prohibited Concomitant Medications and Procedures ....................................................83 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................84 
10.9. 
Appendix 9: Abbreviations and Definitions ...................................................................88 
10.10. 
Appendix 10: Protocol Amendment History ..................................................................92 
11. 
References ......................................................................................................................98 
 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
8 
1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of LY3561774 in Adults with Mixed Dyslipidemia 
Brief Title: 
Efficacy and Safety of LY3561774 Compared with Placebo in Adults with Mixed Dyslipidemia 
Rationale: 
Residual cardiovascular risk is still high, despite the current standard of care that includes 
maximally tolerated statin. Studies show that a reduction in circulating biomarkers, such as non-
HDL-C and apolipoprotein B (ApoB), are associated with a reduction in major cardiovascular 
events. 
This study aims to investigate the impact of LY3561774 on surrogate biomarkers of major 
cardiovascular events in participants with mixed dyslipidemia. This is the first Phase 2 study and 
data from this study will inform dose decisions for the clinical development of LY3561774. 
Overall design: 
This is a Phase 2, randomized, double-blind, placebo-controlled study to investigate the efficacy 
and safety of LY3561774 in adults with mixed dyslipidemia. 
The duration of the study is 270 days with a follow-up visit for some participants at Day 360. 
Brief Summary: 
Screening 
Interested participants will sign the appropriate informed consent document(s) prior to 
completion of any procedures. 
The investigator will review symptoms, risk factors, medical history, concomitant medications 
and other inclusion and exclusion criteria prior to any diagnostic procedures. If the participant is 
eligible after this review, then the site will perform the diagnostic procedures to confirm 
eligibility. 
Double-blind treatment and assessment period 
This part of the study has 11 visits. The two visits after randomization will occur about 15 days 
apart and the remaining visits occur about 30 days apart. 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
9 
This is the general flow during the treatment and assessment period: 
 Complete MRI at any date prior to randomization 
 Complete baseline procedures and sample collection 
 Participants are randomly assigned to an intervention group, and 
 Participants complete all visit procedures including efficacy assessments, safety 
monitoring, study intervention dosing, and post-dosing sample collection. 
Safety follow-up 
If a participant’s ApoB levels do not return to ≥80% of baseline on Day 270, then they will 
continue to the follow-up visit at Day 360. 
If a participant’s ApoB levels return to ≥80% of baseline on Day 270, then Day 270 is their last 
study visit. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
To evaluate if LY3561774 is superior to placebo for 
the treatment of mixed dyslipidemia in adults.  
Percent change from baseline at Day 180 for  
ApoB. 
Secondary 
 
Compare the clinical response of LY3561774 to 
placebo. 
Percent change from baseline at Day 180 for 
 
ANGPTL3 
 
LDL-C 
 
HDL-C 
 
Non-HDL-C, and 
 
Triglycerides.  
Percent change from baseline at Day 270 for 
 
ANGPTL3 
 
Non-HDL-C 
 
LDL-C 
 
HDL-C 
 
ApoB, and 
 
Triglycerides. 
Characterize the pharmacokinetics (PK) of 
LY3561774. 
Plasma concentrations of LY3561774. 
Compare the effect of LY3561774 to placebo on safety 
endpoints. 
Frequency of treatment-emergent adverse events. 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
10 
Objectives 
Endpoints 
To describe the safety of LY3561774 in participants 
with mixed dyslipidemia. 
Summary of safety data, including number and 
incidence of 
 
TEAEs 
 
SAEs, and  
 
Discontinuations due to AEs. 
Abbreviations: AE = adverse event; ANGPTL = angiopoietin-like; Apo = apolipoprotein; HDL-C = high-density 
lipoprotein-cholesterol; LDL-C = low-density lipoprotein cholesterol; SAE = serious adverse event; and TEAE = 
treatment emergent adverse event. 
Estimands 
The primary clinical question of interest is 
What is the treatment difference in ApoB percent change from baseline after 180 days of 
treatment in participants who meet the inclusion criteria and would have completed the 
treatment period? 
The same estimand for the primary objective will be used for the secondary clinical response 
endpoints. 
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3561774 doses with placebo irrespective of adherence to study intervention, including data 
collected during the treatment period and safety follow-up. 
Number of Participants: 
Approximately 175 participants will be randomly assigned in a 2:1:2:2 ratio to placebo: 
LY3561774 100 mg:400 mg:800 mg. Assuming a 20% dropout rate, this results in 
approximately 20 completers for 100 mg group and 40 completers per arm for the rest of the 
groups. 
Intervention Groups and Duration: 
The planned treatment arms are 
 100 mg LY3561774 or placebo 
 400 mg LY3561774 or placebo, and 
 800 mg LY3561774 or placebo. 
Intervention administration is by subcutaneous injection. 
Dosing will occur twice during the study on Day 0 and Day 90 (-5 to +10 days). 
Data Monitoring Committee: No 
 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
11 
1.2. 
Schema  
Approved on 14 Feb 2023 GMT
CCI


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
12 
1.3. 
Schedule of Activities (SoA)  
Screening 
If screening takes longer or shorter than 45 days to complete, it will not be considered a protocol deviation. 
Remote visits 
Visits noted in the SoA are eligible to be conducted remotely at the direction of the sponsor, according to local laws and regulations. 
Remote visits may be by telephone, IT-assisted virtual visit, mobile healthcare, at a local laboratory, or a combination thereof. 
Safety follow-up 
If a participant’s ApoB levels do not return to ≥80% of baseline on Day 270, then the participant will continue to the follow-up visit at 
Day 360. 
If a participant’s ApoB levels return to ≥80% of baseline on Day 270, then Day 270 is their last study visit. 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
The ICF must be signed before any protocol-
specific tests/procedures are performed. See 
Section 10.1.3, for additional details. 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
13 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Inclusion and 
exclusion 
criteria, review 
and confirm 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm inclusion and exclusion criteria prior 
to randomization and administration of first 
dose of study intervention. 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes ethnicity (where permissible), year of 
birth, sex, and race. 
Preexisting 
conditions and 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect all ongoing conditions and relevant past 
surgical and medical history including history 
of premature CV disease. 
Prespecified 
medical history 
(indication and 
history of 
interest) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional data for the indication and 
comorbidities of interest.  
Substance use 
(alcohol) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
14 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Adverse events 
(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 in Section 10.3. If an injection-site 
reaction occurs, collect an additional 
unscheduled immunogenicity and PK sample 
(Section 8.3.4). 
Physical Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant should remove shoes. 
Weight 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes blood pressure and pulse rate. May 
repeat measure once. 
Measure 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 
 
See Section 8.2.1. 
The complete physical examination excludes 
pelvic, rectal, and breast examinations, unless 
clinically indicated.  
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
15 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Symptom-
directed physical 
assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Performed by qualified personnel per local 
regulations based on participant status and 
standard of care. 
Single 12-lead 
ECG 
(local) 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Collect at least 30 minutes 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 investigator’s 
discretion at any visit. 
Schedule MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule MRI prior to randomization for 
applicable participants who meet screening 
inclusion and exclusion criteria. 
MRI 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Performed for the quantification of hepatic fat. 
See Section 8.2.4. 
The participant must fast for at least 6 hours 
prior to the MRI. If they did not fast, schedule 
MRI for another date prior to randomization. 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
16 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Visit 2: Perform MRI at any day prior to 
randomization. 
ED Visit: if ED Visit is prior to Visit 9, then 
conduct MRI. 
If ED Visit is after Visit 9, do not conduct MRI. 
Laboratory Tests and Sample Collections 
On dosing days, collect samples before dosing. 
Hematology 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Clinical 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes non-HDL-C. 
Coagulation 
panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ApoB, ApoA-I, 
ApoC-III 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ANGPTL3 and 
ANGPTL3/8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Insulin 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
UACR 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Urinary albumin/creatinine ratio calculation. 
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Protocol J3F-MC-EZCB(e) 
17 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Serum 
pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only for WOCBP and women with a history of 
tubal ligation. See Section 10.4. 
Urine pregnancy 
(local) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Collect for WOCBP only. 
This test must be performed at Visits 2, 6, 9, 
and end of study with the result available prior 
to first dose of intervention.  
Perform additional pregnancy tests if a 
menstrual period is missed, if there is clinical 
suspicion of pregnancy, or as required by local 
law or regulation. 
FSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional. Perform as needed to confirm 
postmenopausal status. See Section 10.4. 
Hepatitis B virus 
(HBV)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C virus 
(HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated 
glomerular 
filtration rate 
(eGFR) 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Calculated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) 
method. 
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CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
18 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Pharmacokinetic 
(PK) samples 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Visit 2: Collect 2 samples. 
First sample at 0.5 hr post-dose, and 
Second sample: 4-12 hr post-dose (minimum 2 
hr). 
Visit 6: Collect 1 sample any time on the next 
day after 2nd injection, 24-48 hrs post-dose. 
This may require a PK-specific visit. 
Immunogenicity 
(ADA) 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Collect samples before dosing. 
If an immediate or nonimmediate systemic drug 
hypersensitivity reaction occurs, collect an 
additional unscheduled sample as detailed in 
Section 10.2.1. 
PK sample for 
immunogenicity 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
Collect a time-matched PK sample for all 
scheduled and unscheduled immunogenicity 
samples. 
Collect samples before dosing. 
High-sensitivity 
C-reactive 
protein (hsCRP) 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
X 
 
Stored Samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On dosing days, collect samples before dosing. 
Genetic sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol J3F-MC-EZCB(e) 
19 
Study 
J3F-MC-
EZCB(e) 
Screen
ing 
Double-Blind Treatment and Assessment  
 
Follow-
up 
Comments 
Remote Visits 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
V801 on-site for all sites including the US 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
ED 
801 
ED = early discontinuation. 
Days from 
randomization 
-45 
0 
15 
30 
60 
90 
120 
150 
180 
210 
240 
270 
— 
360 
 
Visit interval 
tolerance (days) 
 
— 
±3 
±3 
±3 
-5 
to 
+10 
±7 
±7 
±7 
±7 
±7 
±7 
— 
±7 
Visit 1 procedures may be conducted over more 
than 1 day if all activities are completed within 
the allowable visit tolerance.  
Fasting Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participants should not eat or drink anything 
but water for 8 hours before the visit.  
If a participant arrives not fasted, schedule the 
laboratory draw for another date. 
Exploratory 
biomarker 
samples 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
 
Randomization and Dosing using IWRS 
 
Register visit  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense in 
IWRS 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Dispense 
intervention 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Administer 
intervention 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Abbreviations: ANGPTL = angiopoietin-like; Apo = apolipoprotein; CV = cardiovascular; ECG = electrocardiogram; FSH = follicle-stimulating hormone; ICF = 
informed consent form; IWRS = interactive web-response system; MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone; WOCBP = 
women of childbearing potential. 
 
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Protocol J3F-MC-EZCB(e) 
20 
2. 
Introduction  
LY3561774 
LY3561774 is a novel Dicer-substrate siRNA oligonucleotide designed to reduce the levels of 
ANGPTL3 protein expression. 
How blocking ANGPTL3 reduces lipid levels 
Blocking ANGPTL3 activity or preventing its expression is a potential therapeutic approach to 
reducing ApoB-containing lipoprotein particles that are contributing risk factors for ASCVD 
(Graham et al. 2017; Stitziel et al. 2017). 
Loss-of-function mutations in the ANGPTL3 gene are associated with decreased plasma TGs, 
LDL-C, and HDL-C levels (Graham et al. 2017; Stitziel et al. 2017). In turn, the reduction of 
these atherogenic lipids is expected to result in decreased risk of primary and secondary MACE. 
LY3561774 clinical development 
LY3561774 is being developed as a treatment for patients with mixed dyslipidemia to ultimately 
reduce the risk of MACE. 
2.1. 
Study Rationale  
Residual cardiovascular risk is still high, despite the current standard of care that includes 
maximally tolerated statin. Studies show that a reduction in circulating biomarkers, such as non-
HDL-C and ApoB, are associated with a reduction in MACE (Bowman et al. 2017; Ference et al. 
2019). 
This study aims to investigate the impact of LY3561774 on surrogate biomarkers of MACE in 
participants with mixed dyslipidemia. This is the first Phase 2 study and data from this study will 
inform dose decisions for the clinical development of LY3561774. 
2.2. 
Background  
A detailed description of the chemistry, pharmacology, efficacy, and safety of LY3561774 is 
provided in the IB. 
Clinical Study EZCA preliminary results  
Study J3F-MC-EZCA (EZCA) is a first-in-human study of LY3561774, assessing the safety, 
tolerability, PK, and PD of single-ascending subcutaneous and repeat subcutaneous doses of 
LY3561774 in participants with dyslipidemia. The study had 3 parts that are described in this 
table. 
Study EZCA 
Part 
Subcutaneous dosing 
frequency 
Dose levels 
Number of participants 
at data cut-off date for 
preliminary results 
A 
Single 
24, 72, 208, 480 and  
960 mg 
40 
B 
2 doses given 28 days 
apart 
208 or 480 mg 
16 
C 
Single 
208 or 480 mg 
18 Japanese participantsa 
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Protocol J3F-MC-EZCB(e) 
21 
a Part C was a cohort of only Japanese participants. 
Safety 
Preliminary results suggest LY3561774 is generally well tolerated when administered as single 
doses up to 960 mg and as 2 doses of either 208 or 480 mg. 
Treatment emergent adverse events were mostly mild in severity. 
Part A 
Treatment emergent adverse events reported by at least 2 participants included headache, 
increased blood creatine phosphokinase, and rash. 
After single doses, transient elevations of liver enzymes (AST or ALT >2x ULN) and/or creatine 
kinase (>5x ULN) were observed. These were not associated with any clinical signs or 
symptoms. 
All ISRs resolved spontaneously and there was no apparent relationship of the frequency or 
severity with the dose. 
Part B 
Treatment emergent adverse events reported by at least 2 participants included headache, 
increased hepatic enzymes, and rash. 
No clinically relevant changes in laboratory values were observed. 
Injection-site reactions were reported after administration of 1 dose or repeat dosing, and they 
spontaneously resolved with no apparent relationship to dose. 
Part C 
Treatment emergent adverse events reported by at least 2 participants included ecchymosis. 
One participant had ALT >2x ULN, but less than 3x ULN with no associated clinical signs or 
symptoms. 
Injection-site reactions were reported by 4 participants. 
Pharmacokinetics 
Part A  
After single doses, LY3561774 PK across the tested dose range exhibited 
 linear PK 
 median tmax between 7.5 and 12.5 hours, and 
 mean terminal half-life from 5.5 to 12.9 hours. 
Part B  
After 2 doses, LY3561774 PK exhibited 
 approximate dose proportionality across the dose range tested 
 consistent PK with single-ascending dose cohorts 
 median tmax between 9 and 16 hours after the first dose 
 median tmax between 9 and 10.5 hours after the 2nd dose on Day 29, and 
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Protocol J3F-MC-EZCB(e) 
22 
 a mean t½ of approximately 7 hours. 
Pharmacodynamics  
Dose-dependent decreases in ANGPTL3, TG, and LDL-C were observed after single doses and 2 
doses across the tested dose range. The duration of effect continued up to the last collection time 
point after dosing at Day 169. 
2.3. 
Benefit/Risk Assessment  
Detailed information about the known and expected benefits and risks and reasonably expected 
AEs of LY3561774 may be found in the IB. 
2.3.1. 
Risk Assessment  
Study EZCA clinical data 
Preliminary results from Study EZCA in healthy participants suggest LY3561774 is generally 
well tolerated (See Section 2.2). 
Nonclinical data 
Based on the nonclinical data, LY3561774 is not considered to be a high-risk compound.  
Potential risks 
Based on the current clinical data, nonclinical safety pharmacology and toxicology studies, and 
considering the oligonucleotide class effects, potential risks for clinical study participants 
receiving LY3561774 are hepatobiliary events, systemic allergic or hypersensitivity reactions, or 
ISRs. 
Mitigations for potential risks 
Liver enzyme levels will be monitored at multiple time points and clinical events will be 
monitored closely throughout the study. Participants will also have 2 MRI scans to determine 
change in hepatic fat fraction (see Section 8.2.4). 
Hypersensitivity reactions will be managed per Section 8.3.3. 
Injection-site reaction assessments will occur throughout the study. 
2.3.2. Benefit Assessment  
The efficacy of LY3561774 for lowering lipids has not been established. 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  
Considering the measures taken to minimize risk for the participants in this study, the potential 
risks identified in association with LY3561774 are justified by the anticipated benefits that may 
be afforded to participants with mixed dyslipidemia. 
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Protocol J3F-MC-EZCB(e) 
23 
3. 
Objectives, Endpoints, and Estimands  
Objectives 
Endpoints 
Primary 
 
To evaluate if LY3561774 is superior to placebo for 
the treatment of mixed dyslipidemia in adults.  
Percent change from baseline at Day 180 for  
ApoB. 
Secondary 
 
Compare the clinical response of LY3561774 to 
placebo. 
Percent change from baseline at Day 180 for 
 
ANGPTL3 
 
LDL-C 
 
HDL-C 
 
Non-HDL-C, and 
 
Triglycerides.  
Percent change from baseline at Day 270 for 
 
ANGPTL3 
 
Non-HDL-C 
 
LDL-C 
 
HDL-C 
 
ApoB, and 
 
Triglycerides. 
Characterize the pharmacokinetics (PK) of 
LY3561774. 
Plasma concentrations of LY3561774. 
Compare the effect of LY3561774 to placebo on safety 
endpoints. 
Frequency of treatment-emergent adverse events. 
To describe the safety of LY3561774 in participants 
with mixed dyslipidemia 
Summary of safety data, including number and 
incidence of  
 
TEAEs 
 
SAEs, and 
 
discontinuations due to AEs. 
Exploratory 
 
Assess the relationship between LY3561774 dose and 
clinical endpoints and potential participant factors that 
may influence these relationships. 
Dose-response analyses for key efficacy and safety 
parameters. 
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Protocol J3F-MC-EZCB(e) 
24 
Objectives 
Endpoints 
Assess the relationship between LY3561774 exposure 
and clinical endpoints and potential participant factors 
that may influence these relationships. 
Exposure-response analyses for key efficacy and safety 
parameters. 
Evaluation of immunogenicity.  
Incidence of treatment-emergent anti-drug antibodies 
(ADA).  
Compare the effect of LY3561774 to placebo on 
clinical endpoints or biomarkers. 
Percent change from baseline at Day 180 for 
 
hsCRP 
 
ApoA-I 
 
ApoC-III 
 
VLDL-C 
 
UACR 
 
HbA1c, and 
 
FG. 
Compare the effect of LY3561774 to placebo for key 
efficacy parameters. 
Absolute change from baseline at Day 180 for 
 
Non-HDL-C 
 
LDL-C 
 
HDL-C 
 
ApoB, and 
 
Triglycerides. 
Compare the effect of LY3561774 to placebo on 
hepatic fat fraction. 
Change from baseline for MRI hepatic fat fraction at 
Day 180. 
Abbreviations: AE = adverse event; ANGPTL3 = angiopoietin-like protein 3; Apo = apolipoprotein; FG = fasting 
glucose; HbA1c = hemoglobin A1c; HDL-C = high-density lipoprotein-cholesterol; hsCRP = high-sensitivity C-
reactive protein; LDL-C = low-density lipoprotein-cholesterol; MRI = magnetic resonance imaging; SAE = 
serious adverse event; TEAE = treatment emergent adverse event; UACR = urinary albumin/creatinine ratio; and 
VLDL-C = very-low-density lipoprotein-cholesterol. 
 
 
Primary estimand 
The primary clinical question of interest is 
What is the treatment difference in ApoB percent change from baseline after 180 days of 
treatment in participants who meet the inclusion criteria and would have completed the 
treatment period? 
Efficacy estimand attributes 
This table describes the efficacy estimand attributes. 
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Protocol J3F-MC-EZCB(e) 
25 
Efficacy Estimand Attribute 
Description 
Population 
Participants who meet the inclusion criteria. 
Further details can be found in Sections 5 and 9. 
Endpoint  
Percent change from baseline in ApoB at Day 180. 
Treatment condition  
The randomized treatment. 
Population-level summary  
Difference in mean percent changes in ApoB at Day 
180 between LY3561774 and placebo. 
Intercurrent events 
The intercurrent events including the following are handled by the hypothetical strategy: 
 Permanent discontinuation of intervention. 
 Initiation of excluded medications taken during the study. 
 New initiation of any lipid-lowering drug required to be on a stable regimen prior to 
treatment per the protocol inclusion criteria. 
The potential outcome of interest is the response in the efficacy measurement if participants 
adhere to the randomized treatment. 
Rationale for the efficacy estimand 
This Phase 2 study aims to study the efficacy of LY3561774 under the ideal condition that all 
participants adhere to the randomized treatment. 
Estimand(s) for secondary objectives 
The same estimand for the primary objective will be used for the secondary clinical response 
endpoints. 
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3561774 doses with placebo irrespective of adherence to study intervention, including data 
collected during the treatment period and safety follow-up. 
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Protocol J3F-MC-EZCB(e) 
26 
4. 
Study Design  
4.1. 
Overall Design  
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-arm study to investigate 
the efficacy and safety of LY3561774 in adults with mixed dyslipidemia. 
The planned treatment arms are 
 100 mg LY3561774 or placebo 
 400 mg LY3561774 or placebo, and 
 800 mg LY3561774 or placebo. 
Intervention administration is by subcutaneous injection. 
Dosing will occur twice during the study, on Day 0 and Day 90 (-5 to +10 days). 
4.1.1. 
Design Outline  
Screening 
Interested participants will sign the appropriate informed consent document(s) prior to 
completion of any procedures. 
The investigator will review symptoms, risk factors, medical history, concomitant medications 
and other inclusion and exclusion criteria prior to any diagnostic procedures. If the participant is 
eligible after this review, then the site will perform the diagnostic procedures to confirm 
eligibility. 
Double-blind treatment and assessment period 
This is the general flow during the treatment and assessment period: 
 Complete MRI at any date prior to randomization 
 Complete baseline procedures and sample collection 
 Participants are randomly assigned to an intervention group, and 
 Participants complete all visit procedures including efficacy assessments, safety 
monitoring, study intervention dosing, and post-dosing sample collection. 
Safety follow-up 
If a participant’s ApoB levels do not return to ≥80% of baseline on Day 270, then they will 
continue to the follow-up visit at Day 360. 
If a participant’s ApoB levels return to ≥80% of baseline on Day 270, then Day 270 is their last 
study visit. 
 
 
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Protocol J3F-MC-EZCB(e) 
27 
4.2. 
Scientific Rationale for Study Design  
Primary endpoint 
The primary endpoint, ApoB, is considered the strongest surrogate biomarker and predictor of 
future cardiovascular events. Plasma ApoB levels reflect the number of circulating atherogenic 
ApoB-containing lipoproteins, namely VLDL, intermediate-density lipoprotein, remnants of TG-
rich lipoproteins, LDL, and lipoprotein(a). 
The clinical benefit of lowering both TG and LDL-C levels in patients with mixed dyslipidemia 
appears to be proportional to the absolute change in ApoB (Ference et al. 2019). Even though 
LDL-C and non-HDL-C are good predictors of cardiovascular risk (Puri et al. 2016), more recent 
studies suggest that ApoB may be the primary driver of atherosclerosis and that lowering the 
concentration of all ApoB-containing lipoproteins should be the focus of therapeutic strategies 
(Ference et al. 2020; Richardson et al. 2020; Sniderman et al. 2019; Marston et al. 2022). 
Overall design 
The 270-day duration of the treatment period is based on the demonstrated efficacy and 
prolonged activity of the intervention in the Phase 1 Study EZCA. This duration is also a 
reasonable timeframe to observe efficacy for the treatment of mixed dyslipidemia, which will 
inform the dose level and frequency in future clinical studies. 
The follow-up visit after the last dose is designed to capture any additional safety signals and to 
quantitate the return to baseline for ApoB. 
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 on safety 
assessments and allows a more robust comparison among LY3561774 doses and placebo. 
In this study, collection of demographic information includes ethnicity and race. 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. 
4.3. 
Justification for Dose  
Planned dose levels and frequency for this study 
In this study, the planned subcutaneous doses of 100 mg, 400 mg, and 800 mg will evaluate the 
effect of LY3561774 in participants with mixed dyslipidemia. Dosing will occur twice during the 
study approximately 90 days apart. 
Justification for dose levels and frequency 
The doses and frequency were selected based on human safety, tolerability, PK and PD from 
Phase 1 evaluations, and nonclinical toxicology. Detailed information on these studies may be 
found in the IB. 
The selected dose levels and dosing frequency with prolonged post-dose evaluations of ApoB 
will support a robust dose-exposure-response analysis of multiple safety and efficacy measures. 
Data from this study will support future clinical development of LY3561774. 
 
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Protocol J3F-MC-EZCB(e) 
28 
Phase 1 clinical Study EZCA 
The available clinical safety data from healthy participants after receiving LY3561774 treatment 
up to 960 mg supports continued clinical development in Phase 2. 
LY3561774 treatment up to 960 mg appears to reduce ANGPTL3 and TG levels dose-
dependently. 
Based on a PK/PD model of Study EZCA interim data, the 800 mg dose given every 90 days is 
expected to provide optimal ApoB and non-HDL-C reduction. The 100 mg dose given every 90 
days is chosen as a low efficacy dose to optimize dose-exposure-response analysis. 
Nonclinical toxicology data 
The margin of safety for the 800 mg maximum dose in this study is expected to have an exposure 
multiple of approximately 9.6 times the NOAEL level based on the 6-month, repeat-dose mouse 
toxicity study and 22 times the NOAEL based on the 9-month, repeat-dose monkey toxicity 
study. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of last scheduled procedure shown in the SoA 
(Section 1.3) for the last participant in the trial globally. 
A participant is considered to have completed the study if the participant completes all applicable 
scheduled procedures as shown in the SoA (Section 1.3). 
 
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Protocol J3F-MC-EZCB(e) 
29 
5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Must be 18 years of age or older at the time of signing the informed consent. 
Type of participant and disease characteristics 
2. Have fasting TGs within the range of 150 to 499 mg/dL (1.69 to 5.64 mmol/L) at 
screening. 
3. Have fasting LDL-C >70 mg/dL (1.81 mmol/L) at screening. 
51. Have fasting non-HDL-C >130 mg/dL (3.36 mmol/L) at screening. 
4. Must be on a stable moderate or high-intensity dose of a statin (See Section 10.7.1) for at 
least 2 months before screening and remain on the same medication and dose for the 
duration of the study. 
Weight 
5. Have a body mass index within the range of 18.5 to 40.0 kg/m2, inclusive. 
Sex and contraceptive/barrier requirements 
6.  Are WOCBP who agree to use contraception as outlined in Section 10.4 or  
Are WNOCBP as defined in Section 10.4 or  
Are men who agree to use contraception as outlined in Section 10.4. 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Definitions and contraception requirements for participants in this study are provided in  
Section 10.4. 
Informed consent 
7. Are capable of giving signed informed consent as described in Section 10.1.3, which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol. 
Other inclusions 
8. Have not started a structured weight loss program within 3 months of screening, or plan 
on starting a program during the study. 
9. If taking hypertensive therapy, doses must be stable 30 days prior to screening. 
10. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures. 
11. Have an optimal MRI image quality at screening, as assessed by central laboratory. 
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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Diabetes and cardiovascular medical conditions 
12. Have, in the 6 months prior to screening, uncontrolled Type 1 or Type 2 diabetes, defined 
as an episode of ketoacidosis or hyperosmolar state requiring hospitalization, or 
have an HbA1c ≥8% at screening. 
13. Have a history of nephrotic syndrome. 
14. Have had within the past 3 months prior to screening 
a. Myocardial infarction 
b. Unstable angina 
c. Coronary artery bypass graft 
d. Percutaneous coronary intervention – diagnostic angiograms are permitted 
e. Peripheral artery disease 
f. Transient ischemic attack, or 
g. Cerebrovascular accident. 
15. Have New York Health Association Class III or IV heart failure or last known left 
ventricular ejection fraction <30%. 
16. Have undergone LDL apheresis within 12 months prior to screening. 
Other medical conditions 
17. Have a TSH outside of the 0.4 to 6.0 mIU/L range. 
18. Have a history or presence of an underlying disease, or surgical, physical, or medical 
condition that, in the opinion of the investigator would potentially affect participant 
safety within the study or interfere with the interpretation of data. 
19. Have, within 1 year prior to screening or plan on having during the study, surgical 
treatment for obesity. 
20. Have within 5 years prior to screening a history of an active or untreated malignancy or 
are in remission from a clinically significant malignancy.  
Exceptions: 
 Basal or squamous cell skin cancer. 
 Cervical carcinoma in situ or prostate cancer in situ. 
21. Have a history of or current significant psychiatric disorders considered clinically 
significant in the opinion of the investigator. 
22. Have within 3 years prior to screening a history of chronic alcohol abuse, IV drug abuse, 
or other illicit drug abuse. 
23. Have within 3 months prior to screening used marijuana or tetrahydrocannabinol 
containing products or are unwilling to abstain from use during the study. 
24. Have 2 or more clinically significant or severe drug allergies, or severe post-treatment 
hypersensitivity reactions, including, but not limited to 
a. erythema multiforme major 
b. linear immunoglobulin A dermatosis 
c. toxic epidermal necrolysis, or 
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d. exfoliative dermatitis. 
25. Have a history of acute or chronic pancreatitis. 
26. Have active severe liver diseases, such as cirrhosis, active hepatitis, or biliary obstruction 
with hyperbilirubinemia. 
27. Have a history of infection within 14 days before screening that, in the opinion of the 
investigator, would potentially affect participant safety within the study or interfere with 
the interpretation of data. 
28. Have HIV infection or are positive for HIV antibodies. 
29. Have current infection with hepatitis B virus or positive for hepatitis B surface antigen. 
30. Have a current infection with hepatitis C virus or positive hepatitis C virus antibody. 
Diagnostic assessments 
31. Have clinically relevant anemia, as defined by the investigator. 
32. Have laboratory values, in relation to the reference range,  
ALT >3.0X ULN or  
ALP >1.5X ULN or 
TBL >1.5X ULN, except for participants diagnosed with Gilbert’s syndrome. 
33. Have an eGFR <30 mL/min/1.73 m2. 
34. Have a pulse rate >100 bpm, a repeat measure is allowed. 
35. Have uncontrolled hypertension with a resting blood pressure ≥180 mm Hg systolic 
and/or ≥100 mm Hg diastolic, a repeat measure is allowed. 
Prior/concomitant therapy 
36. Have used or are taking products for the purpose of lowering lipid levels. This includes 
lipid-regulating medication, over-the-counter products, or herbal therapies.  
See Section 10.7.3 for details on prohibited treatments and the timeframe relative to 
screening. 
Exceptions: Statins, PCSK9 inhibitors, bempedoic acid, and ezetimibe. 
37. Have within 3 months of screening, initiated treatment with SERMs, estrogens, 
progestins, testosterone, or thyroid hormone therapy. 
38. Have or are currently taking HIV protease inhibitors, cyclophosphamide, or systemic 
retinoids. 
39. Have within 6 months of screening had treatment with any oligonucleotide, including 
small interfering ribonucleic acid. 
Exception: mRNA vaccines. 
40. Have within 3 months of screening treatment with systemic corticosteroids, cyclosporine, 
isotretinoin, or anabolic agents. 
Exceptions: local, topical, intra-articular, inhalation, or nasal corticosteroids. 
41. Have within 1 month prior to screening treatment with 
a. warfarin or other coumarins 
b. direct thrombin inhibitors 
c. Factor Xa inhibitors, or 
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d. Heparins or heparinoids. 
42. Are currently using a medication associated with weight gain or weight loss. 
Exception: if the participant is on a stable dose for at least 3 months prior to screening 
and will continue the stable dose during the study. 
Prior or concurrent clinical study experience 
43. Are currently enrolled or have participated within the last 6 months in a clinical study 
involving an investigational intervention or any other type of medical research judged not 
to be scientifically or medically compatible with this study. 
44. Have previously completed or withdrawn from this study. 
Other exclusions 
45. Are breastfeeding. 
46. Have an average weekly alcohol intake more than 21 units per week for men and 14 units 
per week for women or are unwilling to stop alcohol consumption from 48 hours prior to 
each visit. 
1 unit of alcohol is equal to 
 12 ounces or 360 mL of beer 
 5 ounces or 150 mL of wine, or 
 1.5 ounces or 45 mL of distilled spirits. 
47. Are unwilling to have an MRI scan or have contraindications for MRI scanning 
a. have a cardiac pacemaker or implants made out of metal, for example, cochlea 
implants, nerve stimulators, magnetic vascular clips, or metallic heart valves 
b. Have extreme claustrophobia 
c. Weight or girth exceeds scanner capabilities, or 
d. In the opinion of the investigator, have any condition or circumstance that would 
interfere with completion of the MRI. 
48. Are Lilly employees or are employees of any third party involved in the study who 
require exclusion of their employees. 
49. 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. 
50. Are unsuitable for inclusion in the study in the opinion of the investigator. 
5.3. 
Lifestyle Considerations  
Participants must not donate blood for the duration of the study and for 8 weeks following 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 
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respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 1 time and require a new identification number. If initial MRI image needs to be 
resubmitted, it will not cause a new identification number to be submitted. If, in the opinion of 
the investigator, an ineligible laboratory test result is the result of an error or extenuating 
circumstance, then that parameter can be retested once without the participant having to be 
rescreened. 
The interval between screenings should be at least 1 week. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable for this study. 
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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, or used by, a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
Each participant will receive either placebo or LY3561774 via subcutaneous injection. 
Intervention Name 
LY3561774  
Placebo 
IMP and NIMP 
IMP 
IMP 
Authorized as defined by 
EU Clinical Trial 
Regulation 
No 
No 
Use 
Experimental 
Placebo-control 
Dose Form 
Solution 
Solution 
Unit Dose Strength(s) 
200 mg/mL 
Not applicable 
Dosage Level(s) 
100 mg 
400 mg 
800 mg 
Not applicable 
Route of Administration 
Subcutaneous injection 
Subcutaneous injection  
Sourcing 
Provided centrally by the sponsor 
Commercially available 0.9% sodium 
chloride solution. 
Labeling 
Study intervention will be labeled as appropriate for country requirements. 
Abbreviations: IMP = investigational medicinal product; NIMP = non-investigational medicinal product. 
 
This table describes the number of injections for the different intervention dose groups. 
Intervention group 
Number of injections  
100 mg or matched placebo participants 
1 injection  
400 mg or matched placebo participants 
1 injection  
800 mg or matched placebo participants 
2 injections 
Location of subcutaneous injections 
All SC injections will be administered into the SC tissue of the abdominal wall, 5 to 10 cm from 
the umbilicus. 
If multiple injections are needed, they will be performed in quick succession and each injection 
should be delivered into separate quadrants in the anterior abdominal wall. 
Record the package number and location of each injection. 
6.2. 
Preparation, Handling, Storage, and Accountability  
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. 
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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. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records). 
Only authorized study personnel may supply, prepare, or administer study intervention. 
Only participants enrolled in the study may receive study intervention. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
Randomization 
All participants will be centrally assigned to randomized study intervention using an IWRS. 
Before the study is initiated, the log in information and directions for the IWRS will be provided 
to each site. 
Participants will be randomly assigned in a 2:1:2:2 ratio to placebo: LY3561774 
100 mg:400 mg:800 mg. 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. 
Participants will be stratified according to the Visit 1 TG level of <250 mg/dL and ≥250 mg/dL. 
Maintaining blinding 
Investigators will remain blinded to each participant’s assigned study intervention within each 
dose group, throughout the course of the study. To maintain this blind, an otherwise unblinded 
third party will be responsible for the receiving, registering, preparing, and administering of all 
study intervention. Although the participant and the investigator will know the injection volume, 
they will not know whether the participant is receiving LY3561774 or placebo. To mitigate the 
risk of unblinding due to color difference between IMPs, site will be trained on additional 
operational procedures. Unblinded personnel who administer IMP to participants at Visit 2 will 
have no other interaction, role, or responsibilities other than receiving, registering, preparing, and 
administering IMP at Visit 6 in the trial. Participants should be instructed to look away during 
IMP administration.  
Emergency unblinding 
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 participant’s 
intervention assignment is warranted. Participant safety must always be the first consideration in 
making such a determination. 
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. 
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Discontinuation from the study in case of unblinding 
If an investigator, study personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from intervention and follow procedures outlined in Section 
7.1. In cases where there are ethical reasons to have the participant remain in the study, the 
investigator must obtain specific approval from a sponsor clinical research physician for the 
participant to continue in the study. 
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 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  
Study intervention will not be available to participants after completion of the study. 
6.7. 
Treatment of Overdose  
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should 
 contact the medical monitor immediately 
 evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted, and 
 closely monitor the participant for any AE/SAE and laboratory abnormalities until 
LY3561774 no longer has a clinical effect. 
6.8. 
Concomitant Therapy  
See Section 10.7 for lists of medications that are permitted or prohibited in this study. 
Concomitant therapy regimens 
All participants should maintain their usual medication regimens for concomitant conditions or 
diseases throughout the study, unless those medications are specifically excluded in the protocol. 
Participants taking concomitant medications should be on stable dosages at the time of screening 
and should remain at stable dosages throughout the study, unless changes need to be made 
because of AEs. 
 
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Changing concomitant therapy 
Participants should consult with authorized study personnel before taking any new medications 
or supplements during the study. Authorized study personnel should consult the sponsor’s 
medical monitor if there are any questions about concomitant therapies during the study. 
The investigator or the participant’s usual diabetes care physician is responsible for changes in 
diabetic medications. 
Concomitant therapy data collection 
For therapy that the participant is receiving at the time of enrollment or receives during the 
study, authorized study personnel should collect 
 the name of medication, vaccine or therapy 
 the reason for use, and 
 dates of administration, including start and end dates. 
For diabetes and lipid modifying medications, such as statins and PCSK9 inhibitors, collect 
dosage information including dose and frequency. 
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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 Section 10.1.9. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. 
Situations when discontinuation of study intervention may occur 
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study 
 a prohibited treatment listed in Section 10.7.3 is initiated during the study, or 
 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 should consult the 
sponsor. 
If study intervention is permanently discontinued, the participant will remain in the study and 
follow procedures for the remaining study visits as shown in the SoA. 
7.1.1. 
Liver Chemistry Stopping Criteria  
The study intervention should be interrupted or discontinued if 1 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  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for intervention interruption or 
discontinuation 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  
In participants with Gilbert’s syndrome, 
doubling of direct bilirubin should be used 
for intervention interruption or 
discontinuation decisions rather than TBL 
>2x ULN. 
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ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Resumption of the study intervention 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, non-intervention etiology is identified. 
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 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 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  
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 enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication. In this case, discontinuation from the study occurs prior to introduction 
of the new agent. 
Discontinuation is expected to be uncommon. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and safety follow-up, if applicable, as shown in the SoA. See 
SoA for data to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed. The participant will be permanently discontinued 
from both the study intervention and the study at that time. 
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. 
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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. 
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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  
8.1.1. 
Primary Efficacy Assessment  
Even though TGs, LDL-C, and non-HDL-C are routinely measured in clinical practices and 
commonly used as primary endpoints in clinical trials for mixed dyslipidemia, ApoB is 
considered the strongest predictor of future cardiovascular events. 
8.1.2. 
Secondary Efficacy Assessments  
At times specified in the SoA, blood samples will be collected to measure changes in levels of 
these markers for mixed dyslipidemia 
 ANGPTL3 
 LDL-C 
 HDL-C 
 Non-HDL-C, and 
 TGs. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
Physical examination at screening 
The complete physical examination will include assessments of these areas and body systems 
 Skin 
o Head 
o Abdomen 
o Extremities 
 Ears, eyes, nose, throat 
 Lymph nodes 
 Thyroid palpation 
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 Cardiovascular 
 Respiratory 
 Gastrointestinal, and 
 Neurologic. 
Height and weight will also be measured and recorded. 
The complete physical examination excludes pelvic, rectal, and breast examinations, unless 
clinically indicated. 
Symptom-directed physical assessments after screening 
These assessments are performed based on participant status and standard of care. 
8.2.2. 
Vital Signs  
Blood pressure and pulse rate will be measured when specified in the SoA and as clinically 
indicated. Additional vital signs may be measured during study visits if warranted, as determined 
by the investigator. 
Vital signs should be measured after participant has been sitting at least 5 minutes, before 
obtaining an ECG tracing, and before collection of blood samples for laboratory testing. 
8.2.3. 
Electrocardiograms  
Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
preferably automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
Electrocardiograms will initially be interpreted by the investigator or qualified designee at the 
site as soon after the time of ECG collection as possible, and ideally while the participant is still 
present, to determine whether the participant meets entry criteria and for immediate participant 
management, should any clinically relevant findings be identified. 
The investigator or qualified designee is responsible for determining if any change in participant 
management is needed and must document their review of the ECG printed at the time of 
evaluation. 
8.2.4. 
Magnetic Resonance Imaging  
Participants will undergo MRI evaluations as outlined in the SoA for the measurement of liver 
fat content. 
Liver fat content will be determined using MRI – Proton Density Fat Fraction. The fat fraction is 
the proportion of mobile protons in liver tissue attributable to fat and is a noninvasive MRI-based 
biomarker of liver TG concentration. 
MRI images will be transmitted to a central reader for evaluation of the MRI-based endpoints. 
For participant safety, images should also be over-read locally to assure there are no underlying 
liver pathologies. 
For participants with claustrophobia in MRI machines, investigators may offer, at their 
discretion, a light sedative. 
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8.2.5. 
Clinical Safety Laboratory Tests  
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA for the 
timing and frequency. 
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 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 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. 
8.2.6. 
Hepatic Monitoring  
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests, including ALT, AST, ALP, TBL, direct bilirubin, GGT, and CK, should be 
repeated within 48 to 72 hours to confirm the abnormality and to determine if it is increasing or 
decreasing, if 1 or more of these conditions occur. This table shows when to repeat laboratory 
tests. 
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 participants 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 participants with Gilbert’s 
syndrome) 
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What to do if the abnormal condition persists or worsens 
If the abnormal liver test result 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 over-the-counter, herbal and dietary 
supplements, and 
 history of alcohol drinking and other substance abuse. 
Frequency of monitoring 
Initially, monitoring of symptoms and liver tests should be done 1 to 3 times weekly, based on 
the participant’s clinical condition and liver test results. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. 
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return to 
approximate baseline levels. 
Comprehensive hepatic evaluation 
When to perform a comprehensive evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of the conditions in this table 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 participants 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 participants with Gilbert’s syndrome)  
aHepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
What a comprehensive evaluation should include 
At a minimum, this evaluation should include 
 physical examination and a thorough medical history, as outlined above 
 tests for 
o PT-INR 
o viral hepatitis A, B, C, or E 
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o autoimmune hepatitis, and 
 an abdominal imaging study, for example, ultrasound or computed tomography 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 
 cytomegalovirus 
 Epstein-Barr virus 
 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 cholangiopancreatography, endoscopic 
retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study 
If a participant develops a hepatic event considered to be an SAE, or discontinues study 
intervention due to a hepatic event, then collect additional hepatic safety data collection in the 
hepatic safety CRFs. 
 
 
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This table shows when to collect additional hepatic safety data based on changes in laboratory 
results. 
If a participant with 
baseline results of...  
develops the following elevations… 
Then… 
Elevated serum ALT 
Collect additional heaptic safety data in 
the hepatic safety CRF. 
ALT <1.5x ULN 
ALT to ≥5x ULN on 2 or more 
consecutive blood tests 
ALT ≥1.5x ULN 
ALT ≥3x baseline on 2 or more 
consecutive blood tests 
Elevated TBL 
TBL <1.5x ULN 
TBL ≥2x ULN (except for participants 
with Gilbert’s syndrome) 
TBL ≥1.5x ULN 
TBL ≥2x baseline  
Elevated ALP 
ALP <1.5x ULN 
ALP ≥2x ULN on 2 or more consecutive 
blood tests 
ALP ≥1.5x ULN 
ALP to ≥2x baseline on 2 or more 
consecutive blood tests 
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.7. 
Pregnancy Testing  
Pregnancy testing will occur throughout the duration of the study as outlined in the SoA. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of these events can be found in Section 10.3. 
 AEs 
 SAEs, and 
 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 the study. 
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 Section 10.3.4. 
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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 informed 
consent 
form (ICF)  
Participation in 
study has ended 
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 with 
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 
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 
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Event 
Collection 
Start 
Collection Stop 
Timing for Reporting to 
Sponsor or Designee 
Mechanism 
for Reporting 
Back-up 
Method 
of 
Reporting 
Pregnancy 
Pregnancy in 
female 
participants 
and female 
partners of 
male 
participants 
After the 
start of 
study 
intervention 
4 days after the last 
dose of intervention 
Within 24 hours  
(see Section 8.3.2) 
Pregnancy 
paper form 
Pregnancy 
paper 
form 
Product Complaints (PCs) 
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 
 
aSerious adverse events 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 LY3561774. 
After learning of a pregnancy in the female partner of a study participant, the investigator will 
obtain a consent to release information from the pregnant female partner directly, and 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. 
Any post-study pregnancy-related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in 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 be withdrawn 
from the study. 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. 
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8.3.3. 
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 Section 10.2.1. Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.4. 
Injection-Site Reactions  
Symptoms and signs of a local 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. 
At the time of ISR occurrence, collect an immunogenicity and PK sample. 
8.3.5. 
Major Adverse Cardiovascular Events (MACE)  
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 
 cardiogenic shock due to myocardial infarction 
 hospitalization for unstable angina 
 hospitalization for heart failure 
 coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention) 
 resuscitated sudden death, and 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack. 
8.4. 
Pharmacokinetics  
Blood samples will be collected for measurement of plasma concentrations of LY3561774 as 
specified in the SoA. 
Participants may need to return to the clinical site for PK-specific visits to provide post-dose PK 
samples dependent on the time window of PK sampling. 
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Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample and the most recent 
LY3561774 dose prior to PK blood draw must be recorded. 
Samples will be used to evaluate the PK of LY3561774. Only samples from participants 
assigned to treatment with LY3561774 will be analyzed for drug concentration. Samples 
collected for analyses may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
Intervention concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel. 
8.4.1. 
Bioanalytical  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. Concentrations of LY3561774 will be assayed using a validated 
bioanalytical method. Analyses of samples collected from placebo-treated participants are not 
planned. 
Sample retention is described in Section 10.1.12. Remaining samples used for PK may be pooled 
and used for exploratory metabolism or bioanalytical method experiments as deemed 
appropriate. 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are described in Section 8.1. 
8.6. 
Genetics  
A whole-blood sample will be collected for pharmacogenetic analysis where local regulations 
allow. See Clinical Laboratory Tests, and the SoA for sample collection information. 
See Section 10.5 for genetic research, custody, and Section 10.1.12 for sample retention 
information. 
8.7. 
Biomarkers  
Serum and plasma samples will be 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 
LY3561774, pathways associated with lipid metabolism, mechanism of action of LY3561774, 
and/or research method, or for validating diagnostic tools or assay(s) related to lipid metabolism. 
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. 
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8.8. 
Immunogenicity Assessments  
Visits and times 
At the visits and times specified in the SoA, venous blood samples will be collected to determine 
antibody production against LY3561774. The actual date and time (24-hour clock time) of each 
sample collection will be recorded. 
Sample collection, handling, and use 
Instructions for the collection and handling of blood samples will be provided by the sponsor. 
Immunogenicity may be assessed by a validated assay designed to detect ADAs in the presence 
of LY3561774 at a laboratory approved by the sponsor. Antibodies may be further characterized 
for their ability to neutralize the activity of LY3561774. 
Samples used for immunogenicity may be used for exploratory analyses as deemed appropriate. 
Sample retention 
Sample retention is described in Appendix 1, Section 10.1.12. 
8.9. 
Health Economics  
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 if LY3561774 100 mg, 400 mg, or 800 mg is 
superior in percent change from baseline for ApoB relative to placebo at Day 180 in participants 
with mixed dyslipidemia. 
9.2. 
Analyses Sets  
This table defines the analysis population and datasets for the purposes of analysis. 
Population 
Description 
Screened  
All participants who signed informed consent. 
Randomized 
All participants who are randomly assigned to a 
treatment arm. 
Efficacy Analysis Set (EAS) 
Data obtained during the treatment period from all 
randomly assigned participants who are exposed to at 
least 1 dose of intervention. Excludes data after 
permanent discontinuation of intervention. Participants 
will be included in the treatment group to which they 
were randomly assigned. 
Full Analysis Set (FAS) 
Data obtained during the treatment period from all 
randomly assigned participants who are exposed to at 
least 1 dose of intervention, regardless of adherence to 
intervention. Participants will be included in the 
treatment group to which they were randomly assigned. 
Safety Analysis Set (SS) 
Data obtained during the treatment period plus safety 
follow-up from all randomly assigned participants who 
are exposed to at least 1 dose of intervention, 
regardless of adherence to intervention. Participants 
will be included in the treatment group to which they 
were randomly assigned. 
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 CSR. Additional exploratory analyses of the data will be conducted as deemed appropriate. 
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and confidence intervals will be calculated at 95%, 2-sided. All tests of interactions 
between treatment groups and other factors will be conducted at a 2-sided alpha level of 0.10. 
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. 
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Primary estimand of interest and efficacy assessment 
The primary estimand is a precise definition of the treatment effect to be estimated. The primary 
estimand of interest is comparing efficacy of LY3561774 doses to placebo and is named the 
“efficacy estimand” (Section 3). The efficacy estimand represents the efficacy prior to 
discontinuation of intervention. 
The primary efficacy assessment guided by the efficacy estimand will be conducted using the 
EAS (Section 9.2). 
Safety assessments 
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3561774 doses with placebo irrespective of adherence to intervention. Thus, safety 
analyses will be conducted using the SS (Section 9.2). 
Exploratory analyses 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
Continuous data 
Continuous data will be summarized by the sample size, mean, SD, median, minimum, and 
maximum. 
Categorical data 
Categorical data will be summarized by sample size, frequency, and percentage. 
Analysis models for the comparison among treatment groups 
The analysis model for comparisons among treatment groups relative to continuous 
measurements assessed over time, in addition to the baseline and end of treatment measurements, 
will be an MMRM. The model terms are 
 treatment 
 visit 
 treatment-by-visit interaction 
 baseline measurement, and 
 Visit 1 TG stratum (<250mg/dL, ≥250 mg/dL). 
Additional covariates may be added and will be detailed in SAP. 
Logistic regression will be used to examine the treatment difference in binary efficacy outcomes. 
Fisher’s exact test or Pearson’s chi-square test will be used to examine the treatment difference 
in categorical outcomes. The negative binomial regression model will be used for the treatment 
comparison of discrete count measures if deemed appropriate. 
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP. 
9.3.2. 
Primary Endpoint/Estimand Analysis  
The primary efficacy assessment, guided by the efficacy estimand, will be conducted using the 
EAS for the primary endpoint. 
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For the efficacy estimand, the hypothetical strategy is used to handle the intercurrent events of 
permanent discontinuation of intervention. 
The primary efficacy comparison will be based on the contrast between each treatment group of 
LY3561774 and placebo for the mean percent change of ApoB from randomization at Visit 2 to 
Day 180 at Visit 9. 
The primary analyses model will be MMRM as described in Section 9.3.1. Treatment 
comparisons will be performed at the full significance level of 0.05. Additional covariates may 
be added, and this analysis will be detailed in the SAP. 
9.3.3. 
Secondary Endpoint(s) Analysis  
Secondary endpoints are listed in Section 3. 
The efficacy analyses for the secondary endpoints will use the EAS and MMRM analysis 
described in Section 9.3.1. The clinical measures for secondary endpoints may be log 
transformed before statistical analyses, if deemed necessary. This analysis will be detailed in 
SAP. 
9.3.4. 
Tertiary/Exploratory Analysis  
Exploratory endpoints are listed in Section 3. 
The average of AUC (Day 120-180) and AUC (Day 210-270) of the ApoB reduction will be 
calculated for participants with complete ApoB measurements during the specified period. 
The calculated AUCs will be analyzed using an ANCOVA model. Baseline ApoB measurements 
will be used for adjustment. A Bayesian approach will be used as the dose-response model for 
time averaged AUC measures. The placebo group will be modeled with LY3561774 doses. 
Details of the prior distribution specifications along with other analyses used 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 LY3561774 doses with 
placebo irrespective of adherence to intervention. Thus, safety analyses will be conducted using 
the SS. 
Adverse events 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. 
 
 
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Summary statistics will be provided for incidence of 
 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 and Vital Signs  
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. 
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 signs, 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  
A population PK approach using nonlinear mixed-effects modeling will be used to summarize 
and analyze LY3561774 concentration data. 
The relationships between LY3561774 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 titers are detected from immunogenicity testing, then the impact of 
immunogenicity titers on LY3561774 PK or any relevant efficacy parameters may also be 
examined. Additional analyses may be conducted if they are deemed appropriate. 
9.3.7. 
Immunogenicity Assessments  
If data from validated immunogenicity assays are available, TE-ADAs may be assessed. 
Treatment-emergent 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 
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 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 LY3561774 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 LY3561774 may also be assessed. Additional details may be provided in the SAP. 
9.3.8. 
Subgroup Analyses  
Subgroup analyses of important factors, such as age, sex, ethnicity, baseline TG, 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  
A first planned interim analysis may be conducted when at least 50% of participants complete 
Day 120 (Visit 7) or discontinue treatment. There may be 2 more interim analyses after the first 
interim analysis and before final analysis (100% of patients complete 180 days of study or 
discontinue treatment). These 3 interim analyses will be for the purpose of internal planning and 
decision making and may assess safety, PK, or efficacy measures. The SAP will describe the 
interim analysis in greater detail. 
If an unplanned interim analysis is deemed necessary for reasons other than a safety concern, the 
protocol must be amended. 
An interim assessment committee (IAC) will be formed to review the interim analyses for 
totality of data including the safety and efficacy reports in an unblinded manner (Section 10.1.5). 
Details on the timing of the interim analyses, operational support, and unblinding will be 
specified in the IAC charter and in the study 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 until final database lock. 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 superiority of LY3561774 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 EZCB will occur when all 
participants have completed 180 days (Visit 9) of treatment. Another efficacy and safety 
assessment will occur when all participants have completed 270 days (Visit 12) 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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9.5. 
Sample Size Determination  
The sample size calculation is based on the primary efficacy estimand and its endpoint, percent 
change from baseline at Day 180 in ApoB. 
Approximately 175 participants will be randomly assigned in a 2:1:2:2 ratio to placebo: 
LY3561774 100 mg:400 mg:800 mg. Assuming a 20% dropout rate, this results in 
approximately 20 completers for 100 mg group and 40 completers per arm for the rest of the 
groups. 
Assuming a standard deviation of 15%, and a 2-sided alpha level of 0.05, the completers for each 
treatment arms will provide >99% power to detect a treatment difference of -30% for the primary 
endpoint. 
 
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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 CIOMS International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
○ Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents (for example, 
advertisements) must be submitted to an 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. 
Investigator sites are compensated for participation in the study as detailed in the CTA. 
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. 
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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. 
10.1.5. 
Committees Structure  
Internal assessment committee (IAC) 
If there are unplanned interim analyses, an IAC will review the interim efficacy and safety data 
in an unblinded fashion. 
The IAC will be fully independent from the study team and will include, at a minimum, a Lilly 
medical physician and a statistician. Details about IAC membership, purpose, responsibilities, 
and operation will be described in an IAC charter, which will be approved prior to the first 
unblinding. 
Participant safety will be continuously monitored by the sponsor’s blinded internal safety review 
team, which includes safety signal detection at any time during the study. 
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All safety data collected will be summarized and reviewed by the sponsor’s internal safety 
review committee for agreement of next steps. 
Evaluation of unblinded safety data by the IAC will occur if any of these events are observed 
following review by the blinded safety review team 
 three or more participants experience hematologic TEAE graded as severe by the 
investigator and are judged as related to blinded study treatment by the investigator 
 three or more participants experience MACE, or 
 
a malignancy SAE occurs during the study. 
Enrollment and dosing may be paused during the review by the IAC. 
Case unblinding may be performed for above reviews if necessary. 
External clinical endpoint committee 
An independent clinical endpoint committee, external to Lilly, will be formed to adjudicate 
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. 
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 for 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, blank or annotated CRFs, 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  
Investigator responsibilities 
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. 
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The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Data monitoring and management 
Quality tolerance limits 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 entered into 
the CRF by authorized study 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 retention and audits 
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 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. 
Electronic data capture system 
An EDC system 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. 
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Data storage and access 
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 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 PC 
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. 
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 
 study termination 
o discontinuation of further study intervention development 
 site termination 
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o 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 
o inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, or 
o 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 
LY3561774 or after LY3561774 become(s) commercially available. 
 
Sample Type 
Custodian 
Retention Period After Last Patient Visita
Exploratory Biomarkers  Sponsor or Designee 
7 years 
PK  
Sponsor or Designee 
1 year 
Genetics  
Sponsor or Designee 
7 years 
Immunogenicity  
Sponsor or Designee 
7 years 
aRetention 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 by the Lilly-designated laboratory or by 
the local laboratory as specified in the table below. 
In circumstances where the sponsor approves local laboratory testing in lieu of Lilly-designated 
laboratory testing, 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. 
 
 
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Clinical Laboratory Tests 
Comments 
Hematology 
Assayed by Lilly-designated laboratory.  
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs - red blood cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration 
 
Leukocytes (WBCs - white blood cells)  
  
Differential  
  
Percent and Absolute Count of: 
 
   Neutrophils, segmented 
  
   Bands 
 
   Lymphocytes 
  
   Monocytes 
  
   Eosinophils 
  
   Basophils 
  
Platelets 
  
Cell morphology (RBC and WBC) 
 
Clinical Chemistry 
Assayed by Lilly-designated laboratory.  
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
Alanine aminotransferase (ALT) 
  
Aspartate aminotransferase (AST) 
  
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) 
  
Creatinine  
  
Creatine kinase (CK) 
Uric acid 
 
Total protein 
  
Albumin 
  
Calcium 
Phosphorus 
Glucose 
  
Amylase 
Lipase 
LDH 
 
Lipid Panel 
Assayed by Lilly-designated laboratory. 
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Clinical Laboratory Tests 
Comments 
After randomization, results will not be provided to 
investigative sites. 
High-density lipoprotein cholesterol (HDL-C) 
 
Non-HDL-C 
 
Low-density lipoprotein cholesterol (LDL-C) 
direct 
 
Very-low-density lipoprotein cholesterol  
(VLDL-C) 
 
Cholesterol 
 
Triglycerides 
 
Coagulation Panel 
Assayed by Lilly-designated laboratory. 
PT-INR 
 
aPTT 
 
Urinalysis 
Assayed by Lilly-designated laboratory. 
Specific gravity 
 
pH 
 
Protein 
 
Glucose 
 
Ketones 
 
Bilirubin 
 
Urobilinogen 
 
Blood 
 
Nitrite 
 
Urine leukocyte esterase 
 
Microscopic examination of sediment 
 
Hormones (female) 
Follicle-stimulating hormone (FSH) 
Assayed by Lilly-designated laboratory. 
Urine pregnancy 
Local laboratory. 
Serum pregnancy 
Assayed by Lilly-designated laboratory. 
Urine Chemistry 
Assayed by Lilly-designated laboratory. 
Albumin 
 
Creatinine 
 
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI) 
 
Urinary albumin/creatinine ratio (UACR) 
 
HIV and Hepatitis Serology 
Assayed by Lilly-designated laboratory. 
HIV testing 
 
Hepatitis C virus (HCV) testing: 
  
    HCV antibody  
 
Hepatitis B virus (HBV) testing:  
 
   Hepatitis B surface antigen (HBsAg)  
 
Pharmacokinetic Samples   
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites. 
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Clinical Laboratory Tests 
Comments 
LY3561774 concentration 
 
Additional Testing 
Assayed by Lilly-designated laboratory. 
HbA1c 
 
C-reactive protein, high-sensitivity (hsCRP) 
Results will not be provided to investigative sites. 
ANGPTL3 and ANGPTL3/8 
Results will not be provided to investigative sites. 
ApoB 
After randomization, only Day 270 results will be provided to 
investigative site. 
ApoA-I, 
Results will not be provided to investigative sites. 
ApoC-III 
Results will not be provided to investigative sites. 
TSH 
 
Insulin 
 
Genetics Sample 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites. 
Exploratory Biomarker Storage Samples  
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites. 
Serum 
  
Plasma (EDTA) 
 
Immunogenicity Samples 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites. 
Anti-LY3561774 antibodies 
 
 
 
 
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10.2.1. 
Laboratory Samples 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 tests 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. 
 
Timing 
Sample Type 
Laboratory Testa 
Collect from 30 minutes to 4 hours 
after the start of the event. 
● 
Note: The optimal collection 
time is 1 to 2 hours after the 
start of event. 
Serum 
total tryptase 
Serum 
complements C3 
Plasma 
compliments C3a and C5a 
Serum 
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine panel 
that includes these 3 cytokines)  
Collect samples on the same day as 
the event. 
If samples were already collected per 
the SoA on the same day as the event, 
then duplicate samples are not 
collected. 
● 
Note: the optimal collection 
time is up to 12 hours after the 
start of the event. 
Serum 
LY3561774 anti-drug antibodies (ADA) 
Plasma 
LY3561774 concentration 
Abbreviation: IL = interleukin. 
aAll 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, and 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. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of 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. 
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 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 and 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). 
 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. 
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e. 
Is a congenital anomaly/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs. 
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 PC 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 PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs 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 PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 
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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/PC 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/PC 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 PC 
information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC 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 PCs. 
 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.  
 
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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. 
 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 healthcare professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any 
post-mortem findings including histopathology. 
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. 
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 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 sponsor by telephone. 
 Contacts for SAE reporting can be found in site training documents. 
 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor. 
 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 site training documents. 
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, 
IRBs/IECs, 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  
Women of childbearing potential 
Adult females are considered WOCBP unless they are WNOCBP. 
Females less than 18 years of age are considered WOCBP if they have 
 they have had at least 1 cycle of menses, or 
 they have Tanner 4 breast development. 
Any amount of spotting should be considered menarche. 
Women not of childbearing potential 
Females are considered WNOCBP if 
 they have a congenital anomaly such as Mullerian agenesis, 
 they are infertile due to surgical sterilization, or 
 they are postmenopausal. 
Examples of surgical sterilization include hysterectomy, bilateral salpingo-oophorectomy, 
bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal 
The postmenopausal state should be defined as: 
 A woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, confirmed by operative note 
OR 
 A woman at least 40 years of age and up to 55 years old with an intact uterus, not on 
hormone therapy*, 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 
 A woman 55 years of age or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea 
OR 
 A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone replacement therapy. 
*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. 
 
 
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10.4.2. 
Contraception Guidance  
Guidance for women of childbearing potential 
This outlines the rules for WOCBP to ensure they do not become pregnant during the study. 
If, as part of their preferred and usual lifestyle, 
WOCBP… 
Then… 
are in a same sex relationship 
 
they must stay in same sex relationships 
without sexual relationships with males, and 
 
take pregnancy tests. 
are completely abstinent 
 
they must agree to remain completely 
abstinent 
are not completely abstinent 
 
they must agree to 
o use 2 forms of contraception, with at 
least 1 form of highly effective 
contraception, and 
o take pregnancy tests. 
Note on forms of contraception: At least 1 form of contraception must be highly effective, meaning 
that it has a less than 1% failure rate. 
Methods of contraception for male participants and their female partners and for women 
of childbearing potential 
Methods 
Examples 
Highly effective 
contraception (less than 
1% failure rate) 
 female sterilization 
 combination oral contraceptive pill 
 progestin-only contraceptive pill (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 
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Note: The barrier method must include use of a spermicide (that 
is, condom with spermicide, diaphragm with spermicide, or 
female condom with spermicide) to be considered effective. 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 
 spermicide alone 
 periodic abstinence 
 fertility awareness (calendar method, temperature method, 
cervical mucus, or symptothermal) 
 withdrawal 
 postcoital douche, or 
 lactational amenorrhea 
Guidance for all men 
All men should refrain from sperm donation for the duration of the study and for the predicted 
time until estimated plasma levels of partner would be below the level of toxicologic concern, 
plus 94 days. 
Men with partners of childbearing potential must 
 either remain abstinent if this is their preferred and usual lifestyle, 
OR 
 use highly effective/effective methods of contraception during intercourse for the 
duration of the study, and 
for the predicted time until estimated plasma levels of partner would be below the level 
of toxicologic concern, plus 94 days. 
Men in exclusively same sex relationship, as their preferred and usual lifestyle are not required to 
use contraception. 
 
 
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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, a blood sample will be collected 
for DNA analysis from consenting participants. 
DNA samples will be used for research related to LY3561774 or mixed dyslipidemia and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related to 
LY3561774 or mixed dyslipidemia and related diseases. Genetic research may consist of the 
analysis of 1 or more candidate genes or the analysis of genetic markers throughout the genome, 
as appropriate. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to LY3561774 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 LY3561774 or study interventions of this class or 
indication continues but no longer than 15 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 
The Lilly-designated laboratory must complete the analysis of all selected testing except for 
microbiology testing. 
Local testing may be performed in addition to Lilly-designated testing when necessary for 
immediate participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) (quantitative) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin A (IgA) (quantitative)  
Hepatitis A virus (HAV) testing: 
Immunoglobulin G (IgG) (quantitative) 
    HAV total antibody 
Immunoglobulin M (IgM) (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) 
a 
    HBV DNA b 
Anti-actin antibody c 
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Hematology 
Clinical Chemistry 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA b 
    EBV DNA b 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNA b 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA 
b 
    HSV (Type 1 and 2) DNA b 
Microbiology 
d 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
    Blood 
 
    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. 
d Assayed ONLY by investigator-designated local laboratory; no Lilly-designated testing available. 
 
 
 
 
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10.7. 
Appendix 7: Concomitant Medication Information  
10.7.1. 
ACC/AHA Statin Therapy List  
This table describes different types of statin therapy by intensity according to the American 
College of Cardiology and the American Heart Association (ACC/AHA) rating system (Stone et 
al. 2014). 
High-Intensity Statin Therapy 
 
Moderate-Intensity Statin Therapy 
 
Daily dose lowers LDL-C by 
approximately ≥50% 
Daily dose lowers LDL-C by 
approximately 30% to <50%  
Atorvastatin 40 mg, 80 mg 
Rosuvastatin 20 mg, 40 mg 
Atorvastatin 10 mg, 20 mg 
Rosuvastatin 5 mg, 10 mg 
Simvastatin 20 mg, 40 mg 
Pravastatin 40 mg, 80 mg 
Lovastatin 40 mg 
Fluvastatin XL 80 mg 
Fluvastatin 40 mg BID 
Pitavastatin 2 mg, 4 mg  
Simvastatin 80 mg is not allowed in this study. 
10.7.2. 
Permitted Concomitant Medications  
This section describes concomitant medications and vaccinations allowed in this study. 
Other medications may be allowed if they are approved by the sponsor or its designee. 
Permitted Concomitant Medications for Study EZCB 
Drug Class 
Comments 
Over-the-counter 
 
Vitamin and mineral supplements 
 
Low-dose aspirin 
 
Occasional acetaminophen or ibuprofen 
 
Corticosteroids 
 
Local, topical, intra-articular, inhalation or nasal 
 
Lipid-regulating medication 
 
Statins 
 
PCSK9 inhibitors 
 
Bempedoic acid 
 
Ezetimibe 
 
Other concomitant treatments 
 
Medications to regulate hypertension 
Participant must be on a stable dose 30 days prior to screening 
Vaccinations 
 
mRNA 
 
Use of live or live attenuated vaccines is permitted up to 
4 weeks before screening. 
 
A non-live or inactivated vaccine is allowed if it is 
received at least 2 weeks before randomization in the 
study or after the last visit. 
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Permitted Concomitant Medications for Study EZCB 
Drug Class 
Comments 
 
Inactivated influenza (“Flu”), pneumococcal, and SARS-
CoV-2 vaccines are allowed during the study. 
Note: It is recommended that study intervention not be 
administered on the same day as a SARS-CoV-2 
vaccination. 
10.7.3. 
Prohibited Concomitant Medications and Procedures  
This section describes medications prohibited in the study. If a prohibited treatment listed here is 
required, the study intervention should be permanently discontinued. 
Prohibited Concomitant Medications and Procedures for Study EZCB 
Drug Class/Procedure 
Comments 
Lipid lowering therapy including, but not limited to: 
 
Triglyceride lowering medication 
o 
Example: Vascepa 
Prohibited within 4 weeks prior to screening 
and during the study.  
 
Simvastatin 80 mg/day 
 
Fibrates 
 
Bile acid sequestrants 
Prohibited within 6 weeks prior to screening 
and during the study. 
 
Over-the-counter and health food preparations 
o 
Examples: red yeast rice, fish oil, omega 3 fatty 
acid >100 mg/day 
 
Niacin >250 to <1000 mg/day or other nicotinic acid 
derivatives 
 
Probucol 
Prohibited within 8 weeks prior to screening 
and during the study. 
 
Niacin >1000 mg/day 
Prohibited within 16 weeks prior to screening 
and during the study. 
 
Inclisiran or any other small interfering ribonucleic acid 
Prohibited within 12 months prior to 
screening and during the study. 
Warfarin or other coumarins 
Prohibited within 1 month prior to screening 
and during the study. 
Direct thrombin inhibitors 
Factor Xa inhibitors 
Heparins or heparinoids 
Systemic corticosteroids, cyclosporine, isotretinoin, or anabolic 
agents 
Exceptions: local, topical, intra-articular, inhalation, or nasal 
corticosteroids 
Prohibited within 3 months prior to screening 
and during the study. 
Anti-sense oligonucleotides 
Exception: mRNA vaccines 
Prohibited within 6 months prior to screening 
and during the study. 
Tamoxifen 
Prohibited  
HIV protease inhibitors, cyclophosphamide or systemic 
retinoids 
Prohibited 
Medications associated with weight gain or loss 
Exception: if participant is on a stable dose for at least 3 
months prior to screening and will continue the stable dose 
during the study. 
Prohibited 
 
 
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10.8. 
Appendix 8: 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. 
Remote visits 
Types of remote visits 
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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) 
 Verification of negative urine pregnancy test, 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. 
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, immunogenicity, ANGPTL3 and 
ANGPTL3/8, ApoB, ApoA-I, ApoC-III, and the lipid panel. 
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Study intervention 
When a participant is unable to go to the site to receive study intervention 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. 
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 intervention. 
 When delivering study intervention 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 intervention. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening visit 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 first screening. 
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 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 
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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, visit types, and conducted 
activities were affected by exceptional circumstances. Dispensing/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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10.9. 
Appendix 9: Abbreviations and Definitions  
 
Term 
Definition 
ADA 
anti-drug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANGPTL 
angiopoietin-like 
Apo 
apolipoprotein 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
blinding 
A single-blind study is one in which the investigator and/or the investigator’s staff are 
aware of the treatment but the participant is not, or vice versa, or when the sponsor is 
aware of the treatment but the investigator and/the investigator’s staff and the 
participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
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. 
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. 
Clinical Research 
Physician 
Individual responsible for the medical conduct of the study. Responsibilities may be 
performed by a physician, clinical research scientist, global safety physician or other 
medical officer. 
CSR 
clinical study report 
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CTA 
clinical trial agreement 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
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. 
FAS 
full analysis set 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
HbA1c 
hemoglobin A1c 
HDL-C 
high-density lipoprotein-cholesterol 
IAC 
internal assessment committee 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
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. 
PT-INR 
Prothrombin Time – International Normalized Ratio 
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/locked. 
intervention 
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. 
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IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ISR 
injection-site reaction 
IWRS 
interactive web-response system 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein-cholesterol 
MACE 
major cardiovascular events 
MMRM 
mixed model for repeated measures 
MRI 
magnetic resonance imaging 
NOAEL 
no-observed-adverse-effect 
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 
PK/PD 
pharmacokinetics/pharmacodynamics 
QTc 
corrected QT interval 
QTLs 
quality tolerance limits 
SAE 
serious adverse event 
SAP 
statistical analysis plan  
SC 
subcutaneous 
SERMs 
selective estrogen receptor modulators 
SS 
safety analysis set 
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.  
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. 
TG 
triglyceride 
tmax 
time of maximum concentration 
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TSH 
thyroid stimulating hormone 
t½ 
terminal half-life 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
WNOCBP 
women not of childbearing potential 
 
 
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10.10. 
Appendix 10: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [d] 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The rationale for the amendment is to clarify how to maintain the blind during IMP 
administration. 
Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
Corrected second WOBCP acronym to be consistent with 
Section 10.4.1 
Accuracy 
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding 
One sentence changed to clarify what third party will be 
responsible for to maintain the blind. Additional sentences 
added to clarify lower risk of unblinding and administering 
IMP. 
Clarification 
Amendment [c] 
This amendment is considered to be substantial because it is likely to have a significant impact 
on the reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
This amendment includes protocol revisions in response to FDA feedback and request for 
changes for Sections 7.1, 9.4, and 10.4.1. Additional changes to the protocol and the 
corresponding rationale for the changes are detailed in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
7.1. Discontinuation 
of Study Intervention 
Changed text to state that participants will 
remain in the study and follow procedures for 
the remaining study visits. 
FDA feedback and request. 
8.3.5. Major Adverse 
Cardiovascular 
Events (MACE) 
Added cardiogenic shock due to myocardial 
infarction and resuscitated sudden death to the 
list of adjudicated events. 
To match the Adjudicated Report & 
Charter. 
9.4. Interim Analysis 
 
Added information about planned interim 
analyses. 
 
Moved text that states that the SAP will 
describe the interim analysis in greater 
detail up near the new text about the 
planned interim analyses. 
 
Added text for unplanned interim analysis. 
 
Removed text that was no longer relevant. 
 
FDA feedback and request 
 
Better readability, and 
 
Updates per Lilly policy. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.2.1. Laboratory 
Samples Obtained at 
the Time of a 
Systemic 
Hypersensitivity 
Event 
 
Corrected the sample type for compliments 
C3a and C5a from serum to plasma. 
 
Correction of sample type. 
10.4.1. Definitions 
Corrected the abbreviation for women not of 
childbearing potential. 
Editorial update. 
Amendment [b] 
This amendment is considered to be substantial because it is likely to have a significant impact 
on the reliability and robustness of the data generated in the clinical study. 
Overall Rationale for the Amendment: 
Recently published data suggest that AngPTL3 inhibition is most likely to be efficacious in 
patients with a relatively more severe risk for cardiovascular disease (Bergmark et al. 2022). As 
such, this amendment includes protocol revisions designed to better target the intervention to 
those who will benefit from it, as well as to streamline the protocol by eliminating one medium-
level dosage and by designating a new, more relevant primary outcome variable. Additional 
changes to the protocol and the corresponding rationale for the changes are detailed in the table 
below. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
Acronym added 
Accuracy  
1.1 Synopsis 
 
Moved ApoB to primary endpoint, 
replaced Non-HDL-C. Changed all Non-
HDL-C to ApoB when referring to 
primary endpoint throughout document. 
 
Changed > 80% to ≥ 80% for ApoB. 
 
Moved non-HDL-C to Secondary 
Endpoint. 
 
Changed Number of Participants from 
225 to 175. 
 
Removed 600 mg arm of study. 
 
Schema changed from non- HDL-C to 
ApoB; 600 mg arm also removed; >80% 
changed to ≥80%.  
 
Study Design Change 
 
 
 
 
For Accuracy 
 
Study Design Change 
 
 
Study Design Change 
 
 
Study Design Change 
 
Study Design Change 
1.2 Schema 
 
Wording for safety follow up changed to 
ApoB 
 
Level changed to ≥ 80% from >80%. 
 
Alignment  
 
 
Study Design Change 
1.3 Schedule of 
Activities 
 
Changed non-HDL-C to ApoB for 
primary endpoint. 
 
United States removed from 
demographics. 
 
 
 
For alignment 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
 
Added urine pregnancy test for Visit 6 
and Visit 9. Comment adjusted 
accordingly.  
 
Ethnicity data collection 
criteria updated from US 
only to where permissible in 
alignment with current data 
collection rules 
 
FDA Feedback  
 3 Objectives, 
Endpoints, and 
Estimands  
 
Changed non-HDL-C to ApoB for 
Primary endpoint. 
 
Moved non-HDL-C to Secondary 
Endpoint. 
 
 
Changed all corresponding Non-HDL-C 
to ApoB when referring to Primary 
Endpoint  
 
Study Design Change 
 
 
Study Design Change 
 
 
 
Study Design Change 
4.1 Overall Design 
 
600 mg arm removed. 
 
Non-HDL-C changed to ApoB. 
 
Study Design Change 
 
Study Design Change  
4.2 Scientific 
Rationale for Study 
Design 
 
Primary Endpoint paragraph wording 
adjusted for using ApoB as Primary 
Endpoint 
 
Non-HDL-C changed to ApoB. 
 
United States removed. 
 
Study Design Change 
 
 
 
Study Design Change 
 
Ethnicity data collection 
criteria updated from US 
only to where permissible in 
alignment with current data 
collection rules 
4.3 Justification for 
Dose 
 
600 mg arm removed. 
 
Non-HDL-C changed to ApoB. 
 
Study Design Change 
 
Study Design Change 
5.1 Inclusion 
Criteria 
 
Non-HDL-C ≥100 mg/dL (2.59 
mmol/L). removed and triglycerides 
levels changed to 200-499 mg/dL for 
IC#2. 
 
Fasting LDL-C changed from >40 
mg/dL to >100 mg/dL and 
corresponding mmol/L number for IC 
#3. 
 
MRI image quality IC #13 added.  
 
Study Design Change 
 
 
 
 
Study Design Change 
 
 
 
 
Study Design Change  
5.4 Screen Failures 
Sentence added to in regard to MRI imaging not 
requiring another identification number.  
Clarification  
6.1 Study 
Intervention(s) 
Administered 
Removed 600 mg arm wording in both tables. 
Study Design Change 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding  
 
Removed 600 mg arm. Ratio adjusted. 
 
 
Changed triglyceride level <225 mg/dL 
to <250 mg/dL. 
 
Changed triglyceride level ≥225 mg/dL 
to ≥ 250 mg/dL. 
 
Study Design Change 
 
 
Study Design Change 
 
 
Study Design Change 
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
95 
Section # and 
Name 
Description of Change 
Brief Rationale 
8.1.1 Primary 
Efficacy 
Assessment 
Non-HDL-C changed to ApoB. 
 
Study Design Change 
8.1.2 Secondary 
Efficacy 
Assessments 
Non-HDL-C changed to ApoB. 
 
Study Design Change 
8.2.7 Pregnancy 
Testing 
Wording added in regard to duration of testing  
Clarification  
9.1 Statistical 
Hypotheses 
 
Removed 600 mg arm. 
 
 
Non-HDL-C changed to ApoB. 
 
Study Design Change 
 
 
Study Design Change 
9.3.1 General 
Considerations 
 
Changed triglyceride level <225 mg/dL 
to <250 mg/dL. 
 
Changed triglyceride level ≥225 mg/dL 
to ≥ 250 mg/dL. 
 
Study Design Change 
 
 
Study Design Change 
9.3.2 Primary 
Endpoint/Estimand 
Analysis 
 
Non-HDL-C changed to ApoB. 
 
 
Sentence on non-HDL-C regarding log 
transformed was removed.  
 
Study Design Change 
 
 
Change in primary endpoint 
 
9.3.4 
Tertiary/Exploratory 
Analysis 
 
Non-HDL-C removed. 
 
Sentence on non-HDL-C regarding log 
transformed was removed.  
 
Study Design Change 
 
Change in primary endpoint 
9.3.5.1 Laboratory 
Measures and Vital 
Signs 
 
Title changed (Electrocardiogram word 
removed. 
 
Selected ECG parameters wording 
removed.  
 
For Accuracy  
 
 
Clarification  
9.3.8 Subgroup 
Analyses 
 
Important factors age, ethnicity added, 
gender wording changed to sex. 
 
Non-HDL-C changed to TG. 
 
Alignment 
 
 
Study Design Change 
9.4 Interim Analysis 
 
Planned interim analysis, Additional 
interim analyses sub-title wording 
removed. 
 
Sentence removed regarding interim 
analyses and data being reviewed. 
 
Added wording to clarify IAC’s data 
analysis. 
 
Sentence added to reference interim 
analysis will be described in SAP. 
 
Formatting 
 
 
 
Clarification 
 
 
Alignment  
 
 
Clarification 
9.5 Sample Size 
Determination 
 
Non-HDL-C changed to ApoB. 
 
Changed Number of Participants from 
225 to 175. 
 
Removed 600 mg arm. 
 
Standard deviation changed from 20% to 
15%. 
 
Study Design Change 
 
Study Design Change 
 
 
Study Design Change 
 
Accuracy  
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
96 
Section # and 
Name 
Description of Change 
Brief Rationale 
10.1.12 Sample 
Retention 
Biomarkers, Genetics, and Immunogenicity 
samples retention period changed from 15 years 
to 7 years; PK sample retention changed from 2 
years to 1 year. 
New Regulations  
10.1.5 Committees 
Structure 
Sentence added in regard to unplanned interim 
analyses for IAC 
Clarification  
10.2 Appendix 2: 
Clinical Laboratory 
Tests 
 
For Lipid Panel, 270-day wording 
removed. 
 
For Coagulation Panel, Assay wording 
added. 
 
For ApoB, only Day 270 results will be 
provided to investigative site.  
 
ApoA-I and ApoC-III placed in their 
own cells  
 
For Accuracy  
 
 
For Accuracy 
 
 
For Accuracy 
 
 
For Accuracy 
10.4 Contraceptive 
and Barrier 
Guidance 
Contraceptive language updated. 
New Guidelines  
10.4.2 
Contraception 
Guidance 
Contraceptive language updated. 
New Guidelines 
11 References 
New References added. 
For Accuracy  
Throughout the 
protocol 
Minor formatting, grammar and editorial changes. 
Minor, therefore, not detailed 
 
 
Amendment [a]: 08-Dec-2021 
Overall Rationale for the Amendment: 
The main rationale for the amendment was to add an immunogenicity (ADA) and related PK 
sample at Visit 2 to the Schedule of Activities.  These samples are needed prior to first dose for 
treatment-emergent ADA analysis. 
Additional changes to the protocol and the corresponding rationale for the changes are detailed in 
the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
In the Brief Summary, added the 
number of visits after randomization 
that will occur about 15 days apart. 
Clarification. 
1.1 Synopsis 
Changed the response for Data 
Monitoring Committee to No. 
No formal DMC will occur for this study. 
1.3 Schedule of 
Activities 
Changed Symptom-directed physical 
examination to Symptom-directed 
physical assessment. 
To better reflect the intent of this procedure 
and qualified personnel. 
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
97 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
Added an immunogenicity (ADA) and 
PK sample for immunogenicity sample 
at Visit 2. 
A sample is needed prior to first dose for 
treatment-emergent ADA analysis. 
6.1 Study 
Intervention(s) 
Administered 
Removed the injection volumes for the 
different intervention groups. 
This information will be provided in the 
pharmacy manual. 
6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Updated text explaining participant 
stratification and changed “baseline” to 
“Visit 1” for triglycerides. 
Clarification. 
8.2.1 Physical 
Examinations 
Changed symptom-directed physical 
examinations to symptom-directed 
physical assessments. 
To better reflect the intent of this procedure 
and qualified personnel, and for consistency 
across the document. 
9.3.1. General 
Considerations for 
statistical analyses 
Updated text explaining the model 
terms and changed “baseline” to “Visit 
1” for triglycerides. 
For consistency with Section 6.3 change. 
 
 
 
Approved on 14 Feb 2023 GMT


CONFIDENTIAL 
Protocol J3F-MC-EZCB(e) 
98 
11. 
References  
Bergmark BA, Marston NA, Bramson CR, et al. Effect of vupanorsen on non-high-density 
lipoprotein cholesterol levels in statin-treated patients with elevated cholesterol: 
TRANSLATE-TIMI 70 [published online April 3, 2022]. Circulation. 
https://doi.org/10.1161/CIRCULATIONAHA.122.059266 
Bowman L, Hopewell JC, Chen F, et al. HPS3/TIMI55–REVEAL Collaborative Group. Effects 
of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 
2017;377(13):1217-1227. https://doi.org/10.1056/NEJMoa1706444 
Ference BA, Kastelein JJP, Catapano AL. Lipids and lipoproteins in 2020. JAMA. 
2020;324(6):595-596. https://doi.org/10.1001/jama.2020.5685 
Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and 
LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA. 2019;321(4):364-
373. https://doi.org/10.1001/jama.2018.20045 
Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 
antisense oligonucleotides. N Engl J Med. 2017;377(3):222-232. 
https://doi.org/10.1056/NEJMoa1701329 
Marston NA, Giugliano RP, Melloni GEM, et al. Association of apolipoprotein B-containing 
lipoproteins and risk of myocardial infarction in individuals with and without atherosclerosis: 
distinguishing between particle concentration, type, and content. JAMA Cardiol. 
2022;7(3):250-256. https://doi.org/10.1001/jamacardio.2021.5083 
Puri R, Nissen SE, Shao M, et al. Non-HDL cholesterol and triglycerides: implications for 
coronary atheroma progression and clinical events. Arterioscler Thromb Vasc Biol. 
2016;36(11):2220-2228. https://doi.org/10.1161/ATVBAHA.116.307601 
Richardson TG, Sanderson E, Palmer TM, et al. Evaluating the relationship between circulating 
lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable 
Mendelian randomisation analysis. PLoS Med. 2020;17(3):e1003062. 
https://doi.org/10.1371/journal.pmed.1003062 
Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B particles and 
cardiovascular disease: a narrative review. JAMA Cardiol. 2019;4(12):1287-1295. 
https://doi.org/10.1001/jamacardio.2019.3780 
Stitziel NO, Khera AV, Wang X, et al. PROMIS and Myocardial Infarction Genetics Consortium 
Investigators. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll 
Cardiol. 2017;69(16):2054-2063. https://doi.org/10.1016/j.jacc.2017.02.030 
Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart 
Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of 
blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines. Circulation. 2014;129(25 Suppl 2):S1-S45. 
https://doi.org/10.1161/01.cir.0000437738.63853.7a 
Approved on 14 Feb 2023 GMT


Signature Page for VV-CLIN-077581 v1.0
Signature Page for VV-CLIN-077581 v1.0
Approval
14-Feb-2023 17:36:23 GMT+0000
Approval
14-Feb-2023 20:03:36 GMT+0000
Approved on 14 Feb 2023 GMT
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan J3F-MC-EZCB (e) 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the 
Efficacy and Safety of  L Y356177 4 in Adults With Mixed Dyslipidemia 
NCT05256654
Approval date: 02-June-2023 


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1  
St atistic al A n al ysis Pl a n  ( J 3 F-M C -E Z C B):  A P h ase 2, R a n d o mi ze d, 
D o u ble -Bli n d, Pl a ce b o -C o ntr olle d St u d y t o I n vesti g ate t he Effic ac y 
a n d S afet y of L Y 3 5 6 1 7 7 4 i n A d ults wit h Mi xe d D ysli pi de mi a  
Pr ot oc ol Title: A P has e 2, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o I n vesti gate 
t he Efficac y a n d Safet y of L Y 3 5 6 1 7 7 4 i n A d ults wit h Mi x e d D ysli pi de mia 
Pr ot oc ol N u m ber: J 3 F-M C -E Z C B  
A me n d me nt N u m ber:  e
C o m p o u n d N u m ber: L Y 3 5 6 1 7 7 4
S h ort Title: E fficac y a n d S afet y of L Y 3 5 6 1 7 7 4  C o m pare d wit h P lace b o i n A d ults wit h Mi x e d 
D ysli pi de mia  
[ Acr o n y m: P R O L O N G -A N G 3 ]  
S p o ns or N a me: Eli Lill y a n d C o m pa n y  
Le g al Re gistere d A d dress: I n di a na p olis, I n dia na, U S A 4 6 2 8 5 
Re g ul at or y A ge nc y I de ntifier N u m ber(s)  
Re gistr y  
I D 
I N D: 1 4 7 3 4 0 
E u dra C T: 2 0 2 1 -0 0 5 4 0 7 -1 3
C o nfi d e nti al I nf or m ati o n  
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s
N ot e t o R e g ul at or y A ut h oriti e s :  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n  r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.  
D oc u me nt I D:  V V -C LI N -0 7 2 1 4 5  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2  
T a ble of C o nte nts  
T a ble of C o nte nts  ...........................................................................................................................2  
Versi o n hist or y  ...............................................................................................................................4  
1.
I ntr o d ucti o n .....................................................................................................................5
1. 1.
O bjecti ves, E n d p oi nts, a n d Esti ma n ds  ..............................................................................5
1. 2.
St u d y Desi g n  .....................................................................................................................9
2.
St atistic al H y p ot heses  ...................................................................................................1 1  
2. 1.
M ulti plicit y A dj ust me nt  ..................................................................................................1 1
3.
A n al ysis Sets  ..................................................................................................................1 2  
4.
St atistic al A n al yses  .......................................................................................................1 3  
4. 1.
Ge neral C o nsi derati o ns  ...................................................................................................1 3
4. 2.
Partici pa nt Dis p ositi o ns  ..................................................................................................1 5
4. 3.
Pri mar y E n d p oi nt A nal ysis  .............................................................................................1 5
4. 3. 1.
Defi niti o n of E n d p oi nt  ....................................................................................................1 6
4. 3. 2.
Mai n A nal ytical A p pr o ac h  ..............................................................................................1 7
4. 4.
Sec o n dar y E n d p oi nts A n al ysis  .......................................................................................1 7
4. 4. 1.
A nal ys es Usi n g t he Effi cac y A nal ysis Set  ......................................................................1 7
4. 5.
E x pl orat or y E n d p oi nts A nal ysis  .....................................................................................1 8
4. 5. 1.
A nal ys es usi n g t h e Efficac y A nal ysis Set  .......................................................................1 8
4. 5. 2.
A nal ys es usi n g t h e F ull A nal ysis Set  ..............................................................................1 9
4. 5. 3.
P har mac o ki netic a n d P har mac o ki netic/ P har mac o d y n a mic 
Met h o ds ...........................................................................................................................1 9
4. 5. 4.
Ba yesi a n A nal yses f or D ose -Res p o nse  ...........................................................................1 9
4. 5. 5.
I m m u n o ge nicit y Assess me nts .........................................................................................2 1
4. 6.
( Ot her) Safet y A nal ys es ..................................................................................................2 1
4. 6. 1.
E xte nt of E x p os ure  ..........................................................................................................2 1
4. 6. 2.
A d verse E v e nts  ...............................................................................................................2 2
4. 6. 3.
Patie nt Narrati ves  ............................................................................................................2 2
4. 6. 4.
Vital Si g ns  .......................................................................................................................2 2
4. 6. 5.
Electr ocar di o gra ms  .........................................................................................................2 4
4. 6. 6.
Cli nical La b orat or y E val uati o n  .......................................................................................2 4
4. 6. 7.
A d diti o nal Safet y Ass ess me nts  .......................................................................................2 4
4. 7.
Ot her A nal yses  ................................................................................................................2 9
4. 8.
I nteri m A nal yses .............................................................................................................3 0
4. 9.
C ha n ges t o Pr ot oc ol -Pla n ne d A nal yses  ..........................................................................3 1
5.
S a m ple Size D eter mi n ati o n  ..........................................................................................3 2  
6.
S u p p orti n g D oc u me nt ati o n  ..........................................................................................3 3  
6. 1.
A p pe n di x 1: De m o gra p hi c a n d Baseli ne C haract eristics  ...............................................3 3
6. 2.
A p pe n di x 2: Hist orical Ill nesses a n d Pree xisti n g C o n diti o ns  .........................................3 3
6. 3.
A p pe n di x 3: Treat me nt C o m plia nce  ...............................................................................3 3
6. 4.
A p pe n di x 4: C o nc o mita nt Me dicati o ns  ..........................................................................3 3
6. 5.
A p pe n di x 5: I m p orta nt Pr ot oc ol De viati o ns  ...................................................................3 4
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 3  
6. 6.  
A p pe n di x 6: Searc hi n g Criteria f or A d diti o nal Safet y 
Assess me nts  ....................................................................................................................3 4  
6. 7.  
A p pe n di x 7: Cli nical La b orat or y E val uati o n  ..................................................................3 6  
6. 8.  
A p pe n di x 8: Defi niti o n of Dia betic Stat us  .....................................................................3 9  
7.  
Refere nces  ......................................................................................................................4 0  
 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 4  
Versi o n hist or y  
T his statistical anal ysis p la n ( S A P) f or S t u d y J 3 F-M C -E Z C B is base d o n pr ot oc ol a me n d me nt 
(e) dat e d 2 4 A u g ust 2 0 2 2.
T a bl e E Z C B. 1 .1  
S A P V er si o n Hi st or y S u m m ar y  
S A P 
Versi o n  
A p pr o v al D ate  
C h a n ge  
R ati o n ale  
1  
See date o n 
Pa ge  1  
N ot A p plica ble  
Ori gi nal v ersi o n  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 5  
1.
I ntr o d ucti o n
1. 1.
O bjecti ves, E n d p oi nts, a n d Esti m a n ds  
T his ta ble descri bes t he o bjecti ves a n d e n d p oi nts  relate d t o St u d y E Z C B. 
O bjecti ves  
E n d p oi nts  
Pri mar y  
T o e val uate if L Y 3 5 6 1 7 7 4 is s u peri or t o 
place b o f or t he treat me nt of mi x e d 
d ysli pi de mia i n a d ults.  
Perce nt c ha n ge fr o m bas eli ne at Da y 1 8 0 f or A p o B.  
Sec o n dar y  
T o c o m pare t h e cli nical r es p o nse of 
L Y 3 5 6 1 7 7 4 t o pla ce b o.  
Perce nt c h a n ge fr o m bas eli ne at Da y 1 8 0 f or 

A N G P T L 3

L D L -C

H D L -C

n o n -H D L -C, a n d

T G .
Perce nt c ha n ge fr o m bas eli ne at Da y 2 7 0 f or  

A N G P T L 3

N o n -H D L -C

L D L -C

H D L -C

A p o B, a n d

T G .
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 6  
T o c haracteriz e t he p h ar mac o ki netics of 
L Y 3 5 6 1 7 7 4.  
Plas ma c o nce ntr ati o ns of L Y 3 5 6 1 7 7 4.  
T o c o m pare t h e effect of L Y 3 5 6 1 7 7 4 t o 
place b o o n safet y e n d p oi nts.  
Fre q u e nc y of treat me nt -e mer ge nt a d verse e v e nts.  
T o descri be t he s afet y of L Y 3 5 6 1 7 7 4 i n 
partici pa nts wit h mi x e d d ysli pi de mia . 
S u m mar y of safet y dat a, i ncl u di n g n u m ber a n d i nci de nce of  

T E A Es,

S A Es, a n d

disc o nti n uati o ns d ue t o A E s.
E x pl orat or y  
T o a ssess t he rel ati o ns hi p bet wee n 
L Y 3 5 6 1 7 7 4 d os e a n d cli nical e n d p oi nts , 
a n d p ote ntial partici pa nt fact ors t hat ma y 
i nfl ue nce t hes e relati o ns hi ps. 
D ose -res p o nse a n al ys es f or ke y efficac y a n d safet y para meters.  
T o assess  t he rel ati o ns hi p bet wee n 
L Y 3 5 6 1 7 7 4 e x p os ure a n d cli nical 
e n d p oi nts , a n d p ote ntial partici pa nt 
fact ors t hat ma y i nfl u e nce t hese 
relati o ns hi ps. 
E x p os ure -res p o nse a n al yses f or ke y efficac y a n d s afet y para meters. 
E val uati o n of i m m u n o ge nicit y. 
I n ci de nce of treat me nt-e mer ge nt A D A.  
T o c o m pare t h e effect of L Y 3 5 6 1 7 7 4 t o 
place b o o n cli nical e n d p oi nts or 
bi o mar kers.  
Perce nt c ha n ge fr o m bas eli ne at Da y 1 8 0 f or  

hs C R P

A p o A -I

A p o C -III

V L D L -C

U A C R
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 7  
 H b A 1c, a n d  
 F G.  
T o c o m pare t h e effect of L Y 3 5 6 1 7 7 4 t o 
place b o f or ke y effic ac y para meters.  
A bs ol ute c ha n ge fr o m baseli ne at Da y 1 8 0 f or  
 N o n -H D L -C  
 L D L -C  
 H D L -C  
 A p o B, a n d  
 T G . 
 
Perce nt c ha n ge fr o m bas eli ne i n ti me -a vera ge d para meters o ver Da ys 3 0  t o 1 8 0 a n d 
Da ys 1 2 0  t o 2 7 0  f or 
 A p o B  
 L D L -C  
 H D L -C  
 N o n -H D L -C  
 T G.  
 T o c o m pare t h e effect of 
L Y 3 5 6 1 7 7 4 t o pla ce b o o n he patic 
fat fracti o n. 
Perce nt a n d a bs ol ute c ha n ge  fr o m baseli ne f or M RI he p atic fat fracti o n at Da y 1 8 0. 
A b bre viati o ns: A D A = a nti -dr u g a nti b o dies; A E = a d verse e ve nt ; A N G P T L 3 = a n gi o p oieti n -li ke pr otei n 3; A p o = a p oli p o pr otei n; A p o A -I = a p oli p o pr otei n A -I; 
A p o B  =  a p oli p o pr otei n  B;  A p o C -III = a p oli p o pr otei n C -III; F G = fasti n g gl uc ose; H b A 1c = he m o gl o bi n A 1c; H D L -C = hi g h -de nsit y li p o pr otei n -c h olester ol; 
hs C R P = hi g h -se nsiti vit y C-re acti ve pr otei n; L D L-C  =  l o w-de nsit y li p o pr otei n -c h olester ol; M RI = ma g netic res o na nce i ma gi n g; S A E = seri o us a d vers e e ve nt; 
T E A E  =  treat me nt-e mer ge nt a d verse e ve nt; T G  =  tri gl yceri d es; U A C R = uri nar y al b u mi n/ creati ni ne rati o ; V L D L -C = ver y -l o w-de nsit y li p o pr otei n -
c h olester ol.  
 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 8  
Pri m ar y esti m a n d  
T he pri mar y cli nic al q uesti o n of i nterest is : w hat is t he treat me nt differe n ce i n  t he a p oli p o pr otei n 
B  (A p o B ) p erce nt c ha n ge fr o m baseli ne after 1 8 0 da ys of treat me nt i n partici pa nts w h o meet t he 
i ncl usi o n criteria a n d w h o w o ul d ha ve c o m plete d t he St u d y E Z C B tr eat me nt peri o d? 
T he  “efficac y esti ma n d” is descri be d b y 
 p o p ulati o n: p artici pa nts w h o meet  t he i ncl usi o n criteria; furt her details ca n be f o u n d i n 
Secti o ns 5 a n d 9  of t he St u d y E Z C B pr ot oc ol  
 en d p oi nt : p erce nt c h a n ge fr o m baseli ne i n A p o B at Da y 1 8 0 , a n d 
 treat me nt c o n diti o n: the ra n d o mize d treat me nt, wit h o ut a n y e x cl u de d me dicati o ns or 
a d diti o nal li pi d-l o weri n g dr u gs. 
T he i nterc urre nt e v e nt s f or St u d y E Z C B  are p er m a ne nt disc o nti n uati o n of i nter ve nti o n , i nitiati o n 
of e x cl u de d me dicati o ns ta ke n d uri n g t he st u d y , a n d ne w i nitiati o n of a n y li pi d-l o weri n g dr u g 
re q uire d t o be o n a sta ble re gi me n pri or t o treat me nt per t he pr ot oc ol i ncl usi o n criteria. T hese are 
ha n dle d b y a h y p ot hetic al strate g y  w here i n the p ote ntial o utc o me of i nterest is t he partici pa nt’s  
res p o nse i n t he efficac y meas ure me nt, if p artici pa nts ha d a d hered  t o t he ra n d o mize d treat me nt. 
T he  p ote ntial o utc o mes r elate d t o t he efficac y esti ma n d are s u m marize d at t he  p o p ulati o n  le vel 
usi n g  t he d iffere n ce i n m ea n perce nt c ha n ges i n A p o B at D a y 1 8 0 bet wee n eac h d ose of 
L Y 3 5 6 1 7 7 4 a n d place b o.  
T he rati o nale f or t his esti ma n d is t o st u d y t h e efficac y of L Y 3 5 6 1 7 7 4 u n der t he i deal c o n diti o n 
t hat all partici pa nts a d here t o t he ra n d o mize d treat me nt. 
E sti m a n d(s) f or sec o n d ar y o bjecti v es  
T he sa me esti ma n d f or t he pri mar y o bjecti ve will be use d f or t h e effi cac y e n d p oi nts f or t he 
sec o n dar y o bj ecti ve of c o m par i n g t he cli nical res p o nse of eac h d ose of L Y 3 5 6 1 7 7 4 t o place b o.  
Sec o n d ar y esti m a n d: tre at me nt -re gi me n esti m a n d 
T he cli nical q uesti o n of i nterest is: w hat is t he treat me nt differe n ce i n ke y li pi d para meters after 
1 8 0 da ys of treat me nt i n partici pa nts w h o meet t h e i ncl usi o n criteria re gar dless of  treat me nt 
disc o nti n uati o n ?  
T he  treat me nt-re gi men  esti ma n d is descri be d b y t he attri b utes  
 p o p ulati o n: p artici pa nts w h o  were ra n d o mize d a n d ha d at least o ne d os e of st u d y 
me dicati o n ; furt her d etails ca n be f o u n d i n Secti o ns 5 a n d 9 of t he  St u d y E Z C B  pr ot oc ol  
 en d p oi nt : p erce nt c h a n ge fr o m baseli ne i n ke y li pi d para meters (l o w-d e nsit y li p o pr otei n -
c h olester ol  [L D L -C ], n o n -hi g h -d e nsit y li p o pr otei n -c h olester ol [n o n -H D L -C ], 
hi g h -de nsit y li p o pr otei n -c h olester ol [H D L -C ], tri gl yceri des [T G ], a n d A p o B) at D a y 1 8 0 , 
a n d 
 treat me nt c o n diti o n: the ra n d o mize d treat me nt , re gar dless of treat me nt disc o nti n uati o n. 
T he  i nterc urre nt e v e nts are ha n dle d b y t he treat me nt p olic y strate g y w here t he p ote ntial o utc o me 
of i nterest is t he res p o nse i n t he effic ac y meas ure me nt re gar dl ess of treat me nt a d here nce.  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 9  
T he p ote ntial o utc o mes r elate d t o t he treat me nt-re gi me n esti ma n d are s u m marize d at t he 
p o p ulati o n  le vel usi n g t h e d iffere nce i n mea n perce nt c ha n ges i n ke y li pi d para meters at Da y 1 8 0 
bet wee n eac h d os e of L Y 3 5 6 1 7 7 4 a n d place b o.  
T he r ati o nale f or this esti ma n d is  t o facilitate a nal ysis base d o n t h e real-w orl d  sce nari o (t hat is, 
t he i nte nti o n-t o-treat pri n ci ple)  f or k e y li pi d para m eters ( L D L-C, n o n -H D L -C, H D L -C,  T G , a n d 
A p o B) . 
U nless  ot her wise  s pecifie d, safet y assess me nts will be g ui de d b y a n esti ma n d c o m pari n g t he 
safet y of L Y 3 5 6 1 7 7 4 d os es wit h place b o irres pecti ve of a d here n ce t o st u d y i nter ve nti o n, 
i ncl u di n g data c ollecte d d uri n g t he treat me nt peri o d a n d safet y f oll o w-u p  (t hat is, t he treat me nt-
re gi me n esti ma n d). 
1. 2.  
St u d y Desi g n   
St u d y E Z C B is a P hase 2, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, p arallel -ar m st u d y t o 
i n vesti gate t he effi cac y a n d safet y of L Y 3 5 6 1 7 7 4 i n a d ults wit h mi x e d d ysli pi de mia. 
Partici pa nts will be ra n d o ml y assi g ne d i n a 2: 1: 2: 2 rati o t o place b o: L Y 3 5 6 1 7 7 4 1 0 0 m g: 4 0 0 
m g: 8 0 0 m g. Pla ce b o partici pa nts will be ra n d o ml y assi g ne d s u c h t hat eac h d ose c o h ort will ha ve 
a matc hi n g place b o c o h ort t hat recei ves t he sa me d ose v ol u me t o mai ntai n t he st u d y bli n d.  
Partici pa nts will be stratifie d acc or di n g t o t he Visit 1 T G le vel of less t ha n 2 5 0 m g/ d L a n d 2 5 0 
m g/ d L or greater . 
St u d y i nter ve nti o n a d mi nistrati o n is b y s u b c uta ne o us i njecti o n.  D osi n g will occ ur t wice d uri n g 
t he st u d y, o n D a y 0 a n d Da y 9 0 ± 5 da ys. 
If a partici pa nt’s A p o B le vels d o n ot ret ur n t o 8 0 % of baseli ne or hi g her o n Da y 2 7 0, t he n t he 
partici pa nt will c o nti n ue t o t he f oll o w -u p visit at Da y 3 6 0.  
If a partici pa nt’s A p o B le vels ret ur n t o ≥8 0 % of b aseli ne or hi g h er  o n Da y 2 7 0, t he n Da y 2 7 0 is 
t he partici pa nt’s last st u d y visit. 
Fi g ure E Z C B. 1 .1  ill ustrates t he st u d y s c he ma.  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 0  
 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T
C CI


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 1  
2.  
St atistic al  H y p ot heses   
T he S t u d y E Z C B h y p ot hesis f or t he pri mar y o bj ecti ve is t hat at least o ne d ose of L Y 3 5 6 1 7 7 4 
1 0 0 m g, 4 0 0 m g, or 8 0 0 m g is s u peri or i n perce nt c ha n ge fr o m baseli ne f or A p o B relati ve t o 
place b o at D a y 1 8 0 i n partici pa nts wit h mi x e d d ysli pi de mia.  
T h us, t he n ull h y p ot hesis t o be teste d i n relati o n t o t he pri mar y esti ma n d is t hat L Y 3 5 6 1 7 7 4 1 0 0 
m g, 4 0 0 m g a n d 8 0 0 m g are n ot differe nt fr o m place b o wit h res p ect t o perce nt c ha n ge i n A p o B 
fr o m baseli ne t o Da y 1 8 0. 
2. 1.  
M ulti plicit y A dj ust me nt   
All t reat me nt c o m paris o ns will be perf or me d at t he f ull si g nifica nce l e vel of 0. 0 5. N o a dj ust me nt 
f or m ulti plicit y will be perf or me d. 
 
 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 2  
3.  
A n al ys is Sets  
T his ta ble defi nes t he a nal ysis p o p ulati o n a n d datasets f or t he p ur p oses of a nal ysis.  
P o p ulati o n  
Descri pti o n  
Scree ne d  
All partici pa nts w h o si g n e d i nf or me d c o ns e nt.  
Ra n d o mize d  
All partici pa nts w h o are ra n d o ml y assi g ne d t o a treat me nt ar m. 
E A S  
Data o btai ne d d uri n g t he treat me nt peri o d fr o m all ra n d o ml y 
assi g ne d p artici pa nts w h o are e x p ose d t o at least 1 d ose of  t he 
st u d y i nter ve nti o n a n d are n ot disc o nti n ue d d ue t o i na d verte nt 
e nr oll me nt . E x cl u des data after a n y of  
 per ma ne nt disc o nti n uati o n of i nter ve nti o n  
 i nitiati o n of e x cl u de d me dicati o ns ta ke n d uri n g t h e 
st u d y, a n d 
 ne w i nitiati o n of a n y li pi d -l o weri n g dr u g re q uire d t o be 
o n a sta ble re gi me n pri or t o treat me nt per t he pr ot oc ol 
i ncl usi o n criteria.  
Partici pa nts will be i ncl u de d i n t he treat me nt gr o u p t o w hic h 
t he y were ra n d o ml y assi g ne d. 
F A S  
Data o btai ne d d uri n g t he treat me nt peri o d fr o m all ra n d o ml y 
assi g ne d p artici pa nts w h o are e x p ose d t o at least 1 d ose of 
st u d y i nter ve nti o n, re gar dless of a d herence t o i nter ve nti o n , a n d 
are n ot disc o nti n ue d d ue t o i na d verte nt e nr oll me nt . Partici pa nts 
will be i ncl u de d i n t he treat me nt gr o u p t o w hic h t he y were 
ra n d o ml y assi g n e d. 
S A S  
Data o btai ne d d uri n g t he treat me nt peri o d pl us safet y f oll o w -u p 
fr o m all ra n d o ml y assi g n e d partici pa nts w h o are e x p ose d t o at 
least 1 d ose of t he st u d y i nter ve nti o n, re gar dless of a d here n ce t o 
t he i nter ve nti o n, a n d are n ot disc o nti n ue d d ue t o i na d verte nt 
e nr oll me nt . Partici pa nts will be i ncl u de d i n t he treat me nt gr o u p 
t o w hic h t he y were ra n d o ml y assi g ne d. 
A b bre viati o ns: E A S = efficac y a nal ysis set; F A S = f ull a nal ysis set; S A S = safet y a nal ysis set.  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 3  
4.  
St atistic al A n al yses   
4. 1.  
Ge ner al C o nsi der ati o ns   
Statistical a nal ysis of t his st u d y will be t he res p o nsi bilit y of Eli Lill y a n d C o m pa n y ( Lill y) or its  
desi g nee. S o me a nal ys es a n d s u m maries descri be d i n t his a nal ysis pla n ma y n ot be c o n d ucte d if  
n ot warra nt e d b y data (f or e x a m ple, t o o fe w e v e nts t o j ustif y c o n d ucti n g a n a nal ysis). A d diti o nal  
e x pl orat or y a n al ys es of t he data ma y b e c o n d uct e d as dee me d a p pr o priat e.  
U nless ot her wise n ote d, all tests of treat me nt effects will be c o n d ucte d at a 2 -si de d al p ha le v el of 
0. 0 5, a n d c o nfi de n ce i nter vals ( CIs) will be calc ul ate d at 9 5 %, 2 -si de d. All tests of i nteracti o ns 
bet wee n tr eat me nt gr o u ps a n d ot her fact ors will be c o n d ucte d at a 2 -si de d al p ha le vel of 0. 1 0. 
U nless state d ot her wise, statistical s u m maries  a n d a nal ys es will be c o n d u cte d base d o n t he 
pla n ne d ra n d o mize d treat me nt gr o u ps: place b o, L Y  1 0 0 m g, L Y 4 0 0 m g , a n d L Y 8 0 0 m g .  
T he pri mar y esti ma n d (a precise d efi niti o n of t he treat me nt effect t o be esti mate d) of i nterest i n 
c o m pari n g t he efficac y of L Y 3 5 6 1 7 7 4  d oses wit h place b o is t he efficac y esti ma n d ( Secti o n  1. 1 ). 
T he pri mar y effic ac y ass ess me nt , g ui de d b y t h e efficac y esti ma n d , will be c o n d ucte d usi n g t he 
effic ac y a n al ysis set ( E A S ) (Secti o n 3 ). S u bjects w h o recei ve d  o nl y t he first d ose of L Y 3 5 6 1 7 7 4 
will be c o nsi dere d  “ o n-tr eat me nt” d uri n g Da y 1 t o Da y 9 0 , w hereas s u bjects w h o recei ve d b ot h 
d oses will be c o nsi dere d “o n -treat me nt” d uri n g t h e e ntire tr eat me nt a n d ass ess me nt peri o d . 
U nless ot her wise  s pecifie d, safet y assess me nts will be g ui de d b y a n esti ma n d c o m pari n g t he 
safet y of L Y 3 5 6 1 7 7 4 d os es wit h place b o , irres pecti ve of a d here nce t o t he st u d y i nter ve nti o n. 
T h us, safet y a n al ys es will be c o n d ucte d usi n g t he safet y a n al ysis set (S A S ) ( Secti o n 3 ). 
F or c o nti n u o us meas ures, s u m mar y statistics will i ncl u de sa m ple siz e, mea n, sta n dar d de viati o n 
(S D ), me dia n, mi ni m u m, a n d ma xi m u m f or b ot h t he act ual a n d t he c ha n ge fr o m baseli ne 
meas ure me nts. L east s q u ares ( L S ) me a ns a n d sta n dar d err ors deri ve d fr o m t he a nal ysis m o dels , 
mi x e d m o del re peate d meas ures ( M M R M) a n d a n al ysis of c o varia n ce  ( A N C O V A) will als o be 
dis pla ye d f or t he c h a n ge fr o m baseli ne meas ure m e nts. Treat me nt c o m p aris o ns will be dis pla ye d 
s h o wi n g L S mea ns  a n d 9 5 % CI s f or treat me nt differe nces, al o n g wit h p-val ues f or treat me nt 
c o m paris o ns.  F or cate g orical meas ur es, s u m mar y statistics will i ncl u de sa m ple siz e, fre q ue nc y, 
a n d perce nta ges.  A l o gistic re gressi o n m o del will be use d t o e xa mi ne t he treat me nt differe nce i n  
bi nar y effi cac y o ut c o mes wit h missi n g e n d p oi nts i m p ute d. Fis her’s e x act test or Pears o n’s  c hi-
s q uare test will be use d f or treat me nt c o m p aris o ns i n ot her cate g orical o utc o mes. 
F or a n al ys es of effic ac y para meters i n v ol vi n g a n A N C O V A m o del, mis si n g dat a will be i m p ute d 
usi n g  t he m ulti ple i m p utati o n met h o d u n der t he m issi n g at ra n d o m ass u m pti o n . S uc h a n 
a p pr oac h is v ali d w he n  t he pr o pe nsit y f or a data p oi nt t o be missi n g is n ot relate d t o t he missi n g 
data, b ut is relate d t o s o me of t he o bser ve d data.  Esti mates a n d sta n dar d err ors fr o m m ulti ple 
i m p ute d datasets will be c o m bi ne d usi n g R u bi n’s r ules. 
E n d p oi nts t hat c o m pare treat me nt gr o u ps bas e d o n  perce nt c ha n ge  fr o m baseli ne will be 
c o n d ucte d b y l o g-tr a nsf or mati o n of t he de pe n d e nt varia bles. Sta n dar d err ors a n d 9 5 % CIs  will be 
c o nstr ucte d  usi n g t he delta met h o d . T he L S m ea ns a n d sta n dar d err or f or eac h treat me nt, 
differe n ce i n L S mea ns b et wee n ar ms, a n d c orres p o n di n g 9 5 % CIs will be calc ulate d as s h o w n i n 
Ta ble  E Z C B. 4 .1 , w h ere 𝑍𝑏 is t he baseli ne of t he l o g of t he res p o nse.  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 4  
T a bl e  E Z C B. 4 .1   
S u m m ar y of R e p ort e d Q u a ntiti e s f or V ari a bl e s R e q uiri n g L o g -
T r a n sf or m ati o n  
Q u a ntit y  
C h a n ge fr o m B aseli ne  
Perce nt C h a n ge fr o m B aseli ne  
Wit hi n 
Treat me nt  
Esti mate  
[e x p ( 𝑍̂Δ Z ,𝑏) −1 ] e x p (𝑍̅𝑏⋅) 
[e x p (𝜇̂Δ Z ,𝑘) −1 ] × 1 0 0  
S E  
e x p (𝑍̅𝑏⋅) e x p (𝜇̂Δ Z ,𝑘) ⋅𝑆𝐸
̂
Δ 𝑍,𝑘 
e x p (𝜇̂Δ Z ,𝑘) ⋅𝑆𝐸
̂
Δ 𝑍,𝑘× 1 0 0  
 
P -val ue  
N R  
𝑝𝑘 
B et wee n -
Treat me nt 
Differe nce  
( Treat me n
t k vs. 
Refere nce 
Ar m)  
Esti mate   
 [e x p ( 𝜇̂Δ Z ,𝑘) −e x p (𝜇̂Δ Z ,𝑅) ] ∙e x p (𝑍̅𝑏⋅) 
(e x p  (𝜇̂Δ 𝑍,𝑘 𝑣𝑠 𝑅) −1 ) × 1 0 0  
S E  
𝑒𝑍̅𝑏⋅√𝑒2 𝜇̂ Δ 𝑍,𝑘⋅( 𝑆𝐸
̂
Δ 𝑍,𝑘)
2 + 𝑒2 𝜇̂ Δ 𝑍,𝑅⋅(𝑆𝐸
̂
Δ 𝑍,𝑅)
2  
 
e x p  (𝜇̂Δ 𝑍,𝑘 𝑣𝑠 𝑅) ⋅𝑆𝐸
̂
Δ 𝑍,𝑘 𝑣𝑠 𝑅× 1 0 0  
P -val ue  
N R  
𝑝Δ 𝑍,𝑘 𝑣𝑠 𝑅 
9 5 % C I 
Esti mate  ± Φ −1 (1 −
𝛼
2 )* S E  
([e x p ( 𝐿∆𝑍,𝑘 𝑣𝑠 𝑅) −1 ] ×
1 0 0 ,[e x p (𝑈∆𝑍,𝑘 𝑣𝑠 𝑅) −1 ] × 1 0 0 ) 
A b bre viati o n: CI = c o nfi de nce i nter val; N R =  n ot re p orte d; S E = sta n dar d err or.  
I n ge neral, a ti me-a v era ge d para m eter will refer t o t he area u n der  t h e c ur ve ( A U C) c o nstr ucte d 
usi n g  t he tra p ez oi dal r ule, a p plie d t o t he para m eter acc or di n g t o t he s c he d ul e d ti me , di vi de d b y 
t he le n gt h of o bs er vati o n. F or e x a m ple , a ti me-a vera ge d de p e n de nt varia ble f or Da ys 3 0 t o 1 8 0 
will  e q ual 𝐴𝑈𝐶/ 1 5 0 , w here 𝐴𝑈𝐶 re pres e nts t he A U C c o nstr ucte d b y t he tra pez oi dal r ule. 
U nless ot her wise s pecifie d, baseli ne is defi ne d as t he last n o n -missi n g meas ure me nt rec or de d o n 
or bef ore t he ra n d o mizati o n visit, pri or t o first d ose of i nter ve nti o n.  
W he n c o nsi deri n g t reat m e nt-e mer ge nt a b n or mal s afet y la b orat or y val ues  a n d vital si g ns , 
baseli ne o bser vati o n will start  fr o m t he scree ni n g visit a n d e n d pri or t o, or at , t he ra n d o mizati o n 
visit , w herei n all sc he d ul e d a n d u nsc he d ule d meas ure me nts will be i ncl u de d. T he b aseli ne f or 
t he treat me nt-e m er ge nt s afet y a n al ysis will be t he ma xi m u m/ mi ni m u m fr o m all meas u re me nts 
ta ke n d uri n g t he bas eli ne peri o d.  F or p ost b aseli ne meas ure me nts, a ll sc h e d ule d a n d u nsc he d ule d 
meas ure me nts i n t he a n al ysis peri o d will be i ncl u d e d.  T he ma xi m u m/ mi ni m u m fr o m all 
meas ure me nts ta k e n d uri n g t he a nal ysis peri o d will be use d i n t he treat me nt-e mer ge nt safet y 
a nal ysis.  T h e e n d of S t u d y E Z C B partici pati o n f or a partici pa nt will be t he earliest of dat e of 
deat h, t he date of wit h dra wal fr o m f urt h er partici pati o n i n t he st u d y, or  t he date of t he safet y 
f oll o w-u p visit ( Visit 8 0 1). F or part ici pa nts c o nsi d ere d t o be l ost t o f oll o w-u p, e n d of S t u d y 
E Z C B partici pati o n will be t he date p artici pa nt is  l ost t o f oll o w-u p  as re p orte d b y t he 
i n vesti gat or. Partici p a nt data i ncl u de d i n t he data base aft er t he last date of S t u d y E Z C B 
partici pati o n (i ncl u di n g t he safet y f oll o w-u p peri o d) will be e x cl u de d fr o m statistical a nal ysis.   
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 5  
Statistical treat me nt c o m paris o ns will o nl y be perf or me d bet wee n L Y 3 5 6 1 7 7 4  d oses a n d 
place b o. Si nce t he tri al is n ot a de q uatel y p o were d t o detect differe nce s a m o n g L Y 3 5 6 1 7 7 4  
d os es, c o m paris o ns acr oss  L Y 3 5 6 1 7 7 4  d os es will n ot be perf or m e d u nless ot her wise s pecifie d.  
N ot all a nal ys es descri be d i n t his S A P will necessaril y b e i ncl u de d i n t he cli nical st u d y re p orts. 
A n y a nal ysis descri b e d i n t his S A P a n d n ot pr o vi de d i n t he cli nical st u d y re p orts will  be 
a vaila ble u p o n re q uest.  
4. 2.  
P artici p a nt Dis p ositi o ns   
A listi n g a n d s u m mar y of S t u d y E Z C B partici pa nt dis p ositi o n f or all ra n d o ml y assi g ne d 
partici pa nts will be  pr o vi de d at t he pri mar y a n d fi nal data base l o c k s, res p ecti vel y. Fre q u e nc y 
c o u nts a n d perce nta ges of all partici pa nts scree n e d, ra n d o ml y assi g n e d, a n d recei vi n g at least 1 
d ose of st u d y dr u g will be prese nt e d b y treat me nt gr o u ps . A listi n g a n d s u m mar y of ra n d o ml y 
assi g ne d  p artici pa nts n ot recei vi n g t he st u d y dr u g will be pr o vi de d. All partici pa nts w h o 
disc o nti n ue S t u d y E Z C B a n d/ or t he st u d y dr u g will be i de ntifie d, a n d t he e xte nt of t heir 
partici pati o n i n S t u d y E Z C B will be re p ort e d. If k n o w n, a reas o n f or t heir disc o nti n uati o n will be 
gi ve n. T h e pri mar y reas o ns f or disc o nti n uati o n will be liste d a n d s u m marize d b y tr eat me nt 
gr o u ps.  
Details a b o ut partici pa nt dis p ositi o ns are i ncl u de d i n t he a p pe n dices: t he de m o gra p hi c a n d 
baseli ne c haracteristics  ( A p pe n di x 1, Secti o n 6. 1 ), hist orical ill nesses a n d pree xisti n g c o n diti o ns 
(A p pe n di x 2,  Secti o n  6. 2 ), treat me nt c o m plia n ce ( A p pe n di x 3, Secti o n  6. 3 ), c o nc o mita nt 
me dicati o ns  (A p pe n di x 4,  Secti o n 6. 4 ), a n d i m p orta nt pr ot oc ol de viati o ns (A p pe n di x 5, Secti o n 
6. 5 ). 
4. 3.  
P ri m ar y E n d p oi nt A n al ysis   
T he pri mar y effic ac y ass ess me nt, g ui de d b y t h e efficac y esti ma n d , will be c o n d ucte d usi n g t he 
effic ac y a n al ysis set ( E A S ) f or t he pri mar y e n d p oi nt ( perce nt c ha n ge fr o m baseli ne at Da y 1 8 0 
f or A p o B). 
T he h y p ot h etical strate g y defi ne d relati ve t o t he efficac y esti ma n d –  ha d partici pa nts a d here d t o 
t he ra n d o mize d treat me nt –  will be use d t o ha n dle t he i nterc urre nt e ve nts  of per ma ne nt 
disc o nti n uati o n of i nter ve nti o n , i nitiati o n of e x cl u de d me dicati o ns ta ke n d uri n g t he st u d y, a n d 
ne w i nitiati o n of a n y li pi d -l o weri n g dr u g re q uire d t o be o n a sta ble re gi me n pri or t o treat me nt per 
t he pr ot oc ol i ncl usi o n criteria. Onl y data c ollecte d bef ore t h e occ urre n ce of a n y i nterc urre nt 
e ve nts will be use d i n t he M M R M a nal ysis. T he M M R M a nal ysis will t he n i m plicitl y i m p ute  t he 
p ote ntial efficac y meas ures (after t he i nterc urre nt e ve nts) if partici pa nts ha d n ot ha d i nterc urre nt 
e ve nts.  
See S ecti o n 1 0. 7. 3 of t he St u d y E Z C B pr ot oc ol f or a list of pr o hi bite d c o nc o mita nt me dicati o ns. 
E x cl u de d me dicati o n a n d li pi d l o weri n g dr u gs a re liste d i n Ta ble E Z C B. 4 .2 . 
 
 
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 6  
T a bl e E Z C B. 4 .2  
Li st of M e di c ati o n s   
Pr o hi b ite d C o nc o mit a nt M e dic ati o ns a n d Pr oce d ures f or St u d y E Z C B 
Dr u g Cl ass/ Pr oce d ure  
C o m me nts  
Li pi d l o weri n g  t hera p y i ncl u di n g, b ut n ot li mite d t o 
 
tri gl yceri de-l o weri n g me dicati o n  
o  
e xa m ple : Vasce pa®  (ic osa p e nt et h yl) 
Pr o hi bite d wit hi n 4 wee ks pri or t o scree ni n g 
a n d d uri n g t he st u d y .  
 
si m vastati n 8 0 m g  per da y  
 
fi brates 
 
b ile aci d se q uestra nts  
Pr o hi bite d wit hi n 6  wee ks pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
 
o ver -t he-c o u nter a n d healt h f o o d pre parati o ns  
o  
e xa m ples: re d yeast rice, fis h oil, o me ga -3 fatt y 
aci d > 1 0 0 m g/ da y  
 
niaci n > 2 5 0 t o < 1 0 0 0 m g/ da y or ot her nic oti nic aci d 
deri vati ves  
 
pr o b uc ol  
Pr o hi bite d wit hi n 8  wee ks pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
 
n iaci n > 1 0 0 0  m g  per da y  
Pr o hi bite d wit hi n 1 6  wee ks pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
 
inclisira n  or a n y ot her s mall i nterferi n g ri b o n ucleic aci d  
Pr o hi bite d wit hi n 1 2 m o nt hs  pri or t o 
scree ni n g a n d d uri n g t he st u d y . 
W arfari n or ot her c o u mari ns  
Pr o hi bite d wit hi n 1 m o nt h  pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
Direct t hr o m bi n i n hi bit ors  
Pr o hi bite d wit hi n 1 m o nt h  pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
Fact or Xa i n hi bit ors  
Pr o hi bite d wit hi n 1 m o nt h  pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
He p ari ns or he p ari n oi ds  
Pr o hi bite d wit hi n 1 m o nt h  pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
S yste mic c ortic oster oi ds, c ycl os p ori ne, is otreti n oi n, or a na b olic 
a ge nts  
E xce pti o ns:  l ocal, t o pical, i ntra-artic ular, i n halati o n, or nas al 
c ortic oster oi ds  
Pr o hi bite d wit hi n 3 m o nt hs  pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
A nti -se nse oli g o n ucle oti des 
E xce pti o n:  m R N A vacci nes  
Pr o hi bite d wit hi n 6 m o nt hs  pri or t o scree ni n g 
a n d d uri n g t he st u d y . 
T a m o xife n  
Pr o hi bite d .  
HI V pr otease i n hi bit ors, c ycl o p h os p ha mi de or s yste mic 
reti n oi ds 
Pr o hi bite d . 
Me dicati o ns ass ociate d wit h wei g ht gai n or l oss  
E xce pti o n:  if partici pa nt is o n a sta ble d ose f or at least 3 
m o nt hs pri or t o scree ni n g a n d will c o nti n ue  ta ki n g a sta ble d ose 
d uri n g t he st u d y.  
Pr o hi bite d . 
 
4. 3. 1.  
Defi niti o n of E n d p oi nt   
T he pri mar y effic ac y c o m paris o n will be base d o n t he c o ntrast bet w ee n eac h treat me nt gr o u p of 
L Y 3 5 6 1 7 7 4 a n d place b o f or t he mea n p erce nt c ha n ge of A p o B bet wee n ra n d o mizati o n at Visit 2 
a n d Da y 1 8 0.  
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 7  
4. 3. 2.  
M ai n A n al ytic al A p pr o ac h   
Mea n perce nt c h a n ge of A p o B  will be a n al yze d usi n g t he M M R M m o del f or t he effi cac y 
esti ma n d. As  descri be d i n Secti o n 4. 1 , t he res p o nse varia ble will be l o g-tra nsf or me d. 
A restricte d ma xi m u m li keli h o o d -base d  M M R M  a nal ysis will be use d t o a nal yze c o nti n u o us 
l o n git u di nal varia bles. All l o n git u di nal o bser vati o ns  ta ke n at eac h sc h e d ule d p ost baseli ne visit 
will be i ncl u de d i n t he a n al ysis. T he m o del f or t he a nal ysis of t he pri mar y efficac y e n d p oi nt of 
perce nt c ha n ge fr o m bas eli ne i n A p o B will i ncl u d e t he fi x e d class effects of treat me nt  gr o u p 
( place b o, L Y 3 5 6 1 7 7 4 1 0 0 m g, L Y 3 5 6 1 7 7 4 4 0 0 m g, a n d L Y 3 5 6 1 7 7 4 8 0 0 m g ), visit, treat me nt-
b y -visit i nteracti o n, Visit 1 T G strat u m (l o wer t ha n 2 5 0  m g/ d L, 2 5 0 m g/ d L  or great er ) as well as 
t he c o nti n u o us baseli ne v al ue of t he l o g-tr a nsf or m e d de pe n d e nt var ia ble. 
A n u nstr uct ure d c o varia n ce str uct ur e will be use d t o m o del t he wit hi n -partici pa nt err ors.  
Si g nifica nce tests will be base d o n L S  m ea ns a n d ty p e III tests. If t his a nal ysis  fails t o c o n ver ge, 
t hese c o varia nce str uct ur es will be teste d i n or der  
 T oe pli tz wit h heter o ge n eit y 
 a ut ore gressi ve wit h heter o ge n eit y  
 c o m p o u n d s y m metr y wit h heter o ge n e o us varia n ces 
 T oe plitz  
 a ut ore gressi ve, a n d  
 c o m p o u n d s y m metr y wit h o ut heter o ge ne o us v aria nces. 
T he first c o varia nce str uct ure t hat c o n ver ges will be use d. T he Ke n war d -R o ger a p pr o xi mati o n  
will be use d t o esti mate de n o mi nat or de grees of free d o m.  
4. 4.  
Sec o n d ar y E n d p oi nts  A n al ysis   
4. 4. 1.  
A n al ys es U si n g t he Effic ac y A n al ysis Set  
T he sec o n d ar y st u d y o bjecti ves will be a nal yze d wit h t he efficac y esti ma n d  usi n g  t he data i n t he 
E A S . T he cli nical  meas ure s f or s ec o n dar y e n d p oi nts ma y be l o g -tr a nsf or m e d bef ore statistical 
a nal ys es, if dee me d necessar y.  
Perce nt c h a n ge fr o m bas eli ne at Da y 1 8 0 f or  
 an gi o p oieti n -li ke pr otei n 3 (A N G P T L 3 )  
 L D L -C  
 H D L -C  
 n o n -H D L -C, a n d  
 T G .  
Perce nt c h a n ge fr o m bas eli ne at Da y 2 7 0 f or  
 A N G P T L 3  
 A p o B  
 L D L -C  
 H D L -C  
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 8  
 n o n -H D L -C, a n d  
 T G . 
Mea n perce nt c h a n ge of t he a b o ve e n d p oi nts will be a nal yz e d usi n g t h e M M R M m o del f or t he 
effic ac y esti ma n d  as d escri be d i n Secti o n 4. 3. 2 . 
4. 5.  
E x pl or at or y E n d p oi nts A n al ysis   
U nless ot her wise s pecifie d, ex pl orat or y a n al ys es will be c o n d ucte d f or t h e E A S  usi n g t he ge n eral  
m et h o ds detaile d i n Secti o n 4. 1 . 
4. 5. 1.  
A n al yses usi n g t he Effic ac y A n al ysis Set   
T he se t w o e x pl orat or y s t u d y o bje cti ves will be a n al yze d usi n g t he E A S a n d t he ass ociate d 
effic ac y esti ma n d.  
Perce nt c h a n ge fr o m bas eli ne at Da y 1 8 0 f or  
 hi g h -se nsiti vit y C-reacti ve pr otei n (hs C R P ) 
 a p oli p o pr otei n A -I (A p o A -I) 
 a p oli p o pr otei n C -III (A p o C -III) 
 V L D L -C  
 uri ne al b u mi n /creati ni ne rati o (U A C R ) 
 he m o gl o bi n A 1c (H b A 1 c ), a n d 
 fasti n g gl uc os e (F G ). 
Perce nt  c h a n ge fr o m bas eli ne  i n ti me-a vera ge d para meters o ver  Da y s 3 0 t o 1 8 0 a n d Da ys 1 2 0  t o 
2 7 0 f or 
 n o n -H D L -C  
 L D L -C  
 H D L -C  
 A p o B, a n d  
 T G . 
T hese e n d p oi nts will be a nal yze d usi n g t he M M R M m o deli n g strate g y as d etaile d i n Secti o n 
4. 3. 2 . C o m paris o ns of differe n ce i n ti me -a v era ge d res p o nse fr o m baseli ne f or treat me nt gr o u p 𝑍 
vers us  place b o refere nce gr o u p, i n d e x e d b y 𝑏, will be ma de b y usi n g c o ntr asts of L S mea ns t o 
calc ulate 
𝑍̂Δ 𝑏= 𝜇̂1 𝑘−𝑍̂1 𝑏+ ∑
𝜇𝑘
𝑆
( 𝐸̂𝑍:𝑘−𝜇̂𝑘:𝑆), 
w here 𝐸̂1 𝑍 is t he c oefficie nt c orres p o n di n g t o treat me nt gr o u p 𝑘, 𝑝̂𝑘:𝜇 c orres p o n ds t o t he 
treat me nt-ti me i nteracti o n c oeffi cie nt, 𝑘 re prese nts t he place b o refere n ce gr o u p, a n d 𝜇𝑅 is t he 
wei g ht at ti me 𝑍 i nf or me d b y t he tra pez oi dal r ule. Esti mates a n d CI s will be c o nstr ucte d fr o m t he 
m o del -base d versi o ns usi n g t he d elta met h o d. A n o verall test of si g nifica n ce will be c o n d ucte d 
usi n g t he F -test u n der t h e n ull h y p ot hesis t hat 𝑏Δ 𝜇= 0  f or all L Y3 5 6 1 7 7 4  ar ms si m ulta ne o usl y.  
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 1 9  
4. 5. 2.  
A n al yses usi n g t he F ull A n al ysis Set   
T he se t w o e x pl orat or y st u d y o bje cti ves will be a n al yze d usi n g t he f ull a n al ysis set (F A S ) a n d t he 
ass ociate d treat me nt -re gi me n esti ma n d. 
A bs ol ute c ha n ge fr o m baseli ne at Da y 1 8 0 f or  
 n o n -H D L -C  
 L D L -C  
 H D L -C  
 A p o B, a n d  
 T G . 
Perce nt  c h a n ge fr o m bas eli ne at Da y 1 8 0 f or  
 n o n -H D L -C  
 L D L -C  
 H D L -C  
 A p o B, a n d  
 T G . 
Missi n g data f or t he de pe n de nt varia bles at eac h ti me p oi nt will be i m p ute d usi n g m ulti ple 
i m p utati o n as detaile d i n Secti o n 4. 1 . 
4. 5. 3.  
P h ar m a c o ki netic a n d P h ar m a c o ki netic/ P h ar m ac o d y n a mic Met h o ds   
P har mac o ki netic ( P K), p har mac o d y n a mic ( P D), a n d P K/ P D a nal ysis are t h e res p o nsi bilit y of 
Lill y’s P K/ P D gr o u p.  
A p o p ulati o n P K a p pr oac h usi n g n o nli near mi x e d -effects m o deli n g will be use d t o a nal yze 
L Y 3 5 6 1 7 7 4 c o nce ntrati o n data.  
E x p os ure -res p o nse a n al ysis bet wee n L Y 3 5 6 1 7 7 4 c o nce ntr ati o n a n d safet y, p har mac o l o g y, a n d 
effic ac y ma y b e perf or m e d usi n g p o p ulati o n P K a n d p o p ulati o n P K/ P D n o nli near mi x e d -effects 
m o deli n g tec h ni q u es i m ple me nte d o n N o nli near Mi x e d Effects M o deli n g ( N O N M E M ® ) 
s oft ware. 
A d diti o nall y, t he i m pact of i ntri nsic a n d e xtri nsic fact ors, s uc h a s a ge, wei g ht, ge n d er, a n d li ver 
f u ncti o n o n P K a n d P D para meters ma y be e x a mi ne d as nee d e d. 
If a nti-dr u g a nti b o d y ( A D A) titers are detecte d fr o m i m m u n o ge nicit y testi n g, t he n t he i m pact of 
i m m u n o ge nicit y titers o n L Y 3 5 6 1 7 7 4 P K, or a n y ot her rele va nt efficac y p ara meters , ma y als o be 
e x a mi ne d. A d diti o nal a nal yses m a y be c o n d u cte d if dee me d a p pr o priate.  
4. 5. 4.  
B a yesi a n A n al yses f or D ose -Res p o nse   
A Ba yesia n d ose -res p o ns e a nal ysis will be perf or me d  o n t he perce nt c ha n ge fr o m baseli ne  at 
Da y 1 8 0  a n d t he p erce nt c ha n ge fr o m baseli ne f or ti me-a vera ge d para meters fr o m Da y 3 0  t o 
Da y 1 8 0  a n d fr o m Da y 1 2 0  t o Da y 2 7 0  f or t he para meters 
 A p o B , a n d 
 n o n -H D L -C . 
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 0  
T he l o n git u di nal m o del, a pr o p orti o nal dis crete ti me m o del ( P D T), will be use d t o esti mate 
Ba yesi a n d ose res p o nse. T he  P D T  m o del ass u mes t hat t he efficac y of t h e m o del le d treat me nt 
platea us aft er s o me ti me p oi nt, 𝑍. Let 𝑏𝑍𝑏(𝜇) re pres e nt t he c ha n ge fr o m baseli ne A p o B at ti me 𝑘 
f or partici pa nt 𝑍 receivi n g d ose 𝑏. T hen  t he P D T ca n be writte n as 
𝜇𝑘𝑆(𝐸) = 𝑍(𝑘𝜇,𝑘,𝑆) + 𝐸(𝑍) ∗𝑘𝑝+ 𝑘𝜇𝑘 
wit h t he mea n f u ncti o n  
𝜇(𝑅𝑍,𝑏,𝜇) = 𝑍(𝑘){𝑣𝑠∗𝑅(𝑒𝑍< 𝑏𝑒) +  𝜇(𝑍𝑘≥𝑆𝐸)} 
w here s i~ N (0 ,σ s
2 ) a n d ϵ it~ N (0 ,σ 2 ),  𝑍= (𝑘(𝑒),𝜇1 ,… ,𝑍𝑅−1 )′,  a n d 𝑆𝐸 re pres e nts t he pr o p orti o n 
of t he effi cac y of d ose le vel 𝑍, 𝑅(𝜇), at ti me 𝑍𝑘, f or 𝑣𝑠< 𝑅𝑆.  Base d o n t he data fr o m t he a b o ve, 
we ma y  ass u me 𝐸𝑍=  D a y 3 0. T he f u ncti o n, 𝑘(𝑣), ma y be s p ecifie d t o all o w  t he err ors t o be  
pr o p orti o nal t o t he ti me tre n d of t he mea n res p o ns e . A n e x a m ple of s uc h a f u ncti o n t hat als o 
i nc or p orates a platea u i n effic ac y ( Q u et al. 2 0 1 9) is 
𝑠(𝑅) = {𝑝𝑍∗𝑘(𝑣𝑠< 𝑅𝛼) +  𝐿(𝑍𝑘≥𝑣𝑠)}. 
A si m ple n or mal d y n a mic li near m o del ma y b e ass u me d f or t he d ose -res p o nse f u ncti o n, 𝑅(𝑈): 
λ (1 ) ~  𝑍(0 ,𝑘𝑣
2 )  
𝑠(𝑅) ~  𝐴(𝑈(𝐶−1 ),𝐴𝑈
2 ) f or 𝐶> 1  
T he esti mati o n of t he para meters will be carrie d o ut i n a Ba yesi a n fra me w or k , ass u mi n g n o n -
i nf or mati ve pri ors f or t h e h y per para meters: 
𝑝𝑙 ~  𝑈(0 ,1 ) 
1 / 𝜎2 ,1 / 𝜎𝑠
2 ,1 /  𝜎𝜆
2  ~  𝐺𝑎𝑚𝑚𝑎(0 .0 1 ,0 .0 1 ) 
P osteri or i nfere n ce will  b e dra w n f or t he d ose  res p o nse at ti me 𝑡 of cli nical i nterest a n d t he 9 5 % 
cre di ble i nter vals will als o be pl otte d.  
Alter nati ve  d ose -res p o ns e m o dels, i ncl u di n g t he three -p ara m eter l o gistic re gressi o n or  p o wer 
m o del , ma y als o be c o nsi dere d  f or 𝜆(𝑑), if t he d ose-res p o nse m o del d o es n ot fit t he data well.  
S o me alter nati ve d ose -res p o nse m o dels are 
 T hree -p ara m eter l o gistic m o del 
λ (d ) = α 0 +
α 1 d ∗
α 2 + d ∗, 
w here  p ara m eters α 0 ,α 1 , a n d α 2  re pres e nt t he basal effect w he n t he d ose le vel is zer o ( place b o), 
t he ma xi m u m effect t hat ca n be ac hie ve d b y a n y d ose le vel o n t o p of place b o, a n d t he d ose le vel 
t hat pr o d uces half of t he ma xi m u m i m pr o ve me nt ( E D5 0 ), res pecti vel y. Here, d ∗, re prese nts t he 
act ual d ose (f or e x a m ple, i n m g) vers us d ose le vel ( 1, 2, 3, a n d s o o n ). 
 P o wer m o del  
λ (d ) = α 0 ∗α 1 d ∗γ  
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 1  
w here  α 0  a n d α 1  re prese nt t he bas al effect f or t he pl ace b o gr o u p  a n d t he sl o pe, res p ecti vel y, a n d 
γ  is a si g m oi dicit y p ara meter i n dicati n g s h a pe or st ee p ness of t he d ose res p o nse.  Here, d ∗, 
re pres e nts t he act u al d ose (f or e x a m ple, i n m g) vers us d ose le vel ( 1, 2, 3, a n d s o o n ). 
F urt her m ore, if t he P D T m o del , or a n y rel ate d l o n git u di nal m o del, d oes n ot fit t he data well,  
t hese or ot her d os e -res p o nse m o dels ma y b e fitte d t o t he perce nt c ha n ge fr o m c ha n ge fr o m 
baseli ne at Da y 1 8 0 , a n d t he perce nt c ha n ge fr o m baseli ne f or ti me-a vera ge d para meters fr o m 
Da y 3 0 t o Da y  1 8 0 a n d fr o m Da y 1 2 0 t o D a y 2 7 0 f or t he para meters , e x cl u di n g t he i nter me di ate 
ti me p oi nts.  
T he sa me d ose -res p o ns e m o dels ma y be fit te d t o t he perce nt a bs ol ute c h a n ge fr o m ba seli ne f or 
ma g n etic res o n a nce i ma gi n g ( M RI ) h e patic fat fracti o n at Da y 1 8 0  a n d t he ti me-a vera ge d 
e n d p oi nts . T hese m o dels will n ot re q uire a d diti o nal l o n git u di nal m o deli n g, a n d will ta ke place 
after i m p utati o n f or missi n g dat a acc or di n g t o t he efficac y est i ma n d f or t he ti me-a vera ge d 
a nal ysis a n d t he treat me nt p olic y esti ma n d f or t h e he patic fat fracti o n a nal ysis . 
4. 5. 5.  
I m m u n o ge nicit y Assess me nts  
If data fr o m vali date d i m m u n o ge nicit y ass a ys are a vaila ble, treat me nt-e mer ge nt -A D As ma y b e 
assesse d.  
Treat me nt -e mer ge nt A D As are d efi ne d as p artici p a nts  
 wit h a 2 -f ol d ( 1 dil uti o n) i ncreas e i n titer t ha n t he mi ni m u m re q uire d dil uti o n if n o A D As 
were d etecte d at baseli ne (treat me nt -i n d uce d A D A), or 
 wit h a 4 -f ol d ( 2 dil uti o ns) i ncrease i n titer c o m pare d wit h baseli ne if A D As were d etecte d 
at baseli ne (treat me nt -b o oste d A D A).  
T he fre q u e nc y a n d perce nta ge of  partici pa nts wit h pree xisti n g A D A a n d w h o are tr eat me nt-
e mer ge nt -A D A p ositi ve ( T E -A D A +) t o L Y 3 5 6 1 7 7 4  will be ta b ulate d.  
T he distri b uti o n of titers  a n d fre q u e nc y of ne utrali zi n g a nti b o dies  (if assess e d) for t he treat me nt-
e mer ge nt -A D A + p artici p a nt s ma y als o be ta b ulate d.  
T he relati o ns hi p bet wee n t he pre se n ce of a nti b o dies a n d P K para meters, efficac y res p o nse, or  
safet y t o L Y 3 5 6 1 7 7 4  ma y als o be assesse d.  
4. 6.  
(Ot her ) S afet y A n al ys es  
U nless ot her wise  s pecifie d, safet y will be assess e d b y c o m p ari n g safet y of L Y 3 5 6 1 7 7 4  d os es  
wit h place b o irres pecti ve of a d here nce t o st u d y dr u g. T h us, safet y a n al ys es will be c o n d ucte d  
usi n g t he S A S . 
4. 6. 1.  
E xte nt of E x p os ure   
D u rati o n of e x p os ure will be calc ulate d as n u m ber of da ys partici pa nt was o n -treat me nt, as 
defi ne d i n S ecti o n 4. 1 . S u m mar y of d urati o n of e x p os ure will be  pr o vi de d b y treat me nt gr o u p 
usi n g data fr o m  t he S A S. T he descri pti ve statistics n, mea n, S D, me dia n, mi ni m u m, ma xi m u m, 
a n d s u m (t hat is, t otal partici pa nt -years of f oll o w -u p ) will be pr o vi de d . I n a d diti o n,  t he n u m ber of 
partici pa nts w h o recei ve d 1 or 2  d oses will be s u m marize d b y c o u nts a n d perce nt a ges. 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 2  
4. 6. 2.  
A d verse E ve nts   
A T E A E is defi ne d as a n e ve nt t hat first occ urre d or w orse n e d i n se verit y after first d ose. T h e 
Me dical Dicti o nar y f or R e g ul at or y Acti vities ( Me d D R A) L o west Le v el Ter m ( L L T) will be use d 
i n t he treat me nt-e mer ge nt deri vati o n. T he ma xi m u m se verit y f or eac h L L T d uri n g t he baseli ne 
peri o d , i ncl u di n g o n g oi n g me dical hist or y, will be use d as baseli ne s e verit y. E ve nts wit h a 
missi n g baseli ne se v erit y will be treate d as “ mil d” i n se verit y f or det er mi ni n g treat me nt -
e mer ge n ce. E v e nts wit h a missi n g se verit y d uri n g t he p ost b aseli ne peri o d will be treate d as 
“se vere” a n d treat me nt -e mer ge nce will be deter mi ne d b y c o m pari n g t o bas eli ne se verit y.  
F or e v e nts occ urri n g o n t he da y of first ta ki n g st u d y me dicati o n, t he cas e re p ort f or m c ollecte d 
i nf or mati o n (f or e x a m ple, treat me nt emer ge nt fla g, start ti me of st u d y treat me nt , a n d e ve nt) will 
be use d t o deter mi ne w het her t he e ve nt w as pre - v ers us p ost -treat me nt if a v aila ble. If t he rele va nt 
i nf or mati o n is n ot a vaila ble, t he n t he e ve nts will be c o u nte d as p osttreat me nt. 
T he c o u nts a n d perce nt a ges of partici pa nts wit h T E A Es will be s u m marize d b y treat me nt usi n g 
Me d D R A Preferre d Ter m ( P T) neste d wit hi n t he S yste m Or ga n Class ( S O C). Statistical 
c o m paris o ns will be a p plie d at b ot h t he S O C a n d P T le vels. E ve nts will be or dere d b y d ecreasi n g 
fre q ue n c y wit hi n S O C. T he S O C will be i n al p ha betical or der. F or e ve nts t hat are s e x-s pecific, 
t he de n o mi nat or a n d c o m p utati o n of t he perce nta ge will i ncl u de o nl y p artici pa nts fr o m t he gi v e n 
se x. 
A n o ver vie w of t he n u m ber a n d perce nta ge of partici pa nts w h o  e x perie nce d a T E A E, seri o us 
a d verse e ve nt  ( A E), deat h, disc o nti n ue d fr o m st u d y treat me nt or st u d y d ue t o a n A E, a n d T E A E 
relati o ns hi p t o st u d y dr u g will be s u m marize d b y treat me nt. 
T he c o u nts a n d perce nt a ges of patie nts wit h T E A Es b y ma xi m u m se verit y will  be s u m marize d 
b y treat me nt usi n g M e d D R A P T. F or eac h partici pa nt a n d T E A E, t he ma xi m u m se verit y f or t he 
Me d D R A P T is t he ma xi m u m p ost baseli ne se verit y o bser ve d fr o m all ass ociate d L L Ts ma p pi n g 
t o t he Me d D R A P T. T he ma xi m u m se verit y will b e deter mi ne d b ase d o n t h e n o n -missi n g 
se verities. If all se verities are missi n g f or t he defi n e d p ost baseli ne peri o d of i nterest, it will s h o w 
as missi n g i n t he ta ble.  
4. 6. 3.  
P ati e nt N arr ati ves   
Patie nt n arrati ves  c o nt ai n patie nt le vel data a n d a s u m mar y p ara gra p h.  Patie nt narrati ves will be 
pr o vi de d f or p artici pa nts i n t he ra n d o mize d p o p ulati o n wit h at least o ne n ota ble e ve nt . N ot a ble 
e ve nts i ncl u de deat h, seri o us a d verse e ve nts, a n d p er ma ne nt disc o nti n uati o n of st u d y tr eat me nt 
d ue t o a n a d verse e v e nt.   
4. 6. 4.  
Vit al Si g ns   
If m ulti ple rec or ds of a p artici pa nt’s  vital si g ns are c oll ecte d at t he sa me visit, t he y will be 
a vera ge d pri or t o bei n g use d f or data s u m maries a n d a nal ys es.  
Descri pti ve s u m maries b y treat me nt a n d b y n o mi nal visit will be pr o vi de d f or baseli ne a n d 
p ost baseli ne val ues as w ell as c ha n ge fr o m bas eli ne val ues.  
Treat m e nt differe n ces i n mea n c ha n ge will be a n al yz e d usi n g t he M M R M m o del as descri be d i n 
Secti o n 4. 3. 2   
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 3  
C o u nts a n d perce nta ges of partici pa nts wit h treat me nt-e mer ge nt a b n or mal sitti n g s yst olic bl o o d 
press ure ( B P), sitti n g diast olic B P, a n d p ulse rate will be prese nte d b y tr eat me nt gr o u p. B ot h 
pla n ne d a n d u n pla n n e d meas ure me nts will be i ncl u de d i n t he a nal ysi s. C o u nts a n d perce nta ges of 
partici pa nts wit h treat me nt -e mer ge nt a b n or mal sitti n g s yst olic bl o o d press ure ( B P), sitti n g 
diast olic B P, a n d p ulse will be prese nte d b y tre at me nt f or partici p a nts w h o ha ve b ot h baseli ne 
a n d at least 1 p ost baseli n e res ult. A treat me nt-e mer ge nt  hi g h res ult is defi ne d as a c ha n ge fr o m a 
val ue less t ha n or e q u al t o t he hi g h li mit at baseli ne , t o a val ue greater t ha n t he hi g h li mit at a n y 
ti me, t hat meets t he s pecifie d c ha n ge criteria d uri n g t he p ost bas eli ne peri o d. A treat me nt-
e mer ge nt l o w res ult is defi ne d as a c ha n ge fr o m a val ue greater t ha n or e q u al t o t he l o w li mit at 
baseli ne , t o a val ue l ess t ha n t he l o w li mit at a n y ti me, t hat meets t he s pecifie d c ha n ge criteria 
d uri n g t he p ost bas eli ne p eri o d. T o assess decreases, c ha n ge fr o m t he mi ni m u m val ue d uri n g t he 
baseli ne peri o d t o t he mi ni m u m val ue d uri n g t he p ost baseli ne peri o d will be use d. T o assess 
i ncreas es, c ha n ges fr o m t he ma xi m u m val ue d uri n g t he baseli ne peri o d t o t he ma xi m u m val ue 
d uri n g t he p ost bas eli ne p eri o d will be use d. B ot h pla n ne d a n d u n pla n ne d meas ure me nts will be 
i ncl u de d i n t he a nal ysis. T he criteri a f or i de ntif yi n g patie nts wit h treat me nt -e mer ge nt vital si g n 
a b n or malities are st ate d i n  Ta ble E Z C B. 4 .3 .  
T a bl e E Z C B. 4 .3   
C at e g ori c al Crit eri a f or A b n or m al Tr e at m e nt -E m er g e nt Bl o o d 
Pr e s s ur e a n d P ul s e M e a s ur e m e nt s   
P ar a meter  
L o w  
Hi g h  
S yst olic B P ( m m H g)  
(s u pi ne or sitti n g) 
≤9 0 a n d decrease fr o m 
baseli ne  ≥2 0  
≥1 2 9  a n d i ncrease fr o m 
baseli ne  ≥2 0  
Diast olic B P ( m m H g)  
(s upi ne or  sitti n g) 
≤5 0 a n d decrease fr o m 
baseli ne  ≥1 0  
≥9 0 a n d i ncrease fr o m 
baseli ne  ≥1 0  
P ulse ( b p m)  
(s u pi ne or sitti n g) 
< 5 0 a n d decrease fr o m 
baseli ne  ≥1 5  
> 1 0 0 a n d i ncrease fr o m 
baseli ne  ≥1 5  
W ei g ht ( k g)  
( L oss) Decrease ≥7 %  
( Gai n) I ncrease ≥7 %  
A b bre viati o ns: B P = bl o o d press ure; b p m = beats per mi n ut e . 
C o u nts a n d perce nta ges of partici pa nts wit h ma xi m u m s yst olic bl o o d press ure a n d diast olic 
bl o o d press ure will be s u m marize d b y treat me nt gr o u ps f or t he cate g ories  liste d i n Ta ble  E Z C B  
4 .4 , usi n g t he S A S .  
T a bl e  E Z C B  4 .4  
C at e g ori c al Crit eri a f or S u m m ari e s of M a xi m u m Bl o o d Pr e s s ur e   
S yst olic B P ( m m H g)  
Di ast olic B P ( m m H g)  
< 9 0  
< 6 0  
≥9 0  
> 6 0  
≥1 2 0  
> 9 0  
≥1 4 0  
> 1 1 0  
≥1 6 0  
≥1 2 0  
≥1 8 0  
- 
A b bre viati o n: B P = bl o o d press ure.  
 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 4  
4. 6. 5.  
Electr oc a r di o gr a ms   
Treat me nt -e mer ge nt q u alitati ve electr ocar di o gra m ( E C G ) a b n or m alities are defi ne d as 
q ualitati ve a b n or malities t hat first occ urre d after t h e first d ose of st u d y i nter ve nti o n . Q ualitati ve 
a b n or mal E C Gs will be rec or de d as A Es . A listi n g of q ualitati ve E CGs ma y be pr o d uce d.  
4. 6. 6.  
Cli nic al L a b or at or y E v al u ati o n   
All la b orat or y data will be re p ort e d i n SI u nits. Sel ecte d la b orat or y meas ures will als o be 
re p orte d usi n g c o n v e nti o nal u nits. Li mits fr o m t he perf or mi n g la b will be use d t o defi ne l o w ( L) 
a n d hi g h ( H). Descri pti ve s u m maries b y tr eat me nt a n d b y n o mi nal visit will be pr o vi de d f or t he 
baseli ne a n d p ost baseli ne val ues , as well as t he c h a n ge fr o m b aseli ne val ues.  
O bser ve d a n d c ha n ge f r o m baseli ne val ues f or eac h visit ma y b e dis pla ye d i n pl ots f or 
partici pa nts w h o ha v e b ot h a baseli ne a n d at least 1 p ost baseli ne pla n ne d m eas ure m e nt. Bas eli ne 
will be t he last n o n -missi n g o bser vati o n pri or t o ta ki n g t he first st u d y dr u g. U n pla n ne d 
meas ur e me nts will be e x cl u de d fr o m pl ots.  
A s hift ta ble will be pr o vi de d i ncl u di n g u n pla n ne d meas ure me nts. T h e s hift ta ble will i ncl u de t he 
n u m ber a n d perce nt a ge of partici pa nts wit hi n eac h baseli ne cat e g or y (l o w, n or mal, hi g h, or 
missi n g) vers us eac h p ost baseli ne cate g or y (l o w, n or mal, hi g h, or missi n g) b y treat me nt. T he 
pr o p orti o n of partici pa nts s hifte d will be c o m pare d bet wee n tr eat me nts usi n g Fis her’s e x act test.  
F or q ualitati ve la b orat or y a nal yt es, t he n u m ber a n d perce nt a ge of partici pa nts wit h n or mal a n d 
ab n or mal val ues will be s u m marize d b y treat me nt.  
A listi n g of a b n or mal fi n di n gs will be create d f or la b orat or y a n al yt e meas ure me nts, i ncl u di n g 
q ualitati ve meas ures. T h e listi n g will i ncl u de partici pa nt i de ntificati o n, treat me nt gr o u p, 
la b orat or y c ollecti o n date, st u d y da y, a nal yt e na me, a n d a nal yte fi n di n g.  
Usi n g t he S A S , the  M M R M m o del  as descri be d i n S ecti o n 4. 3. 2  will be use d f or t he a nal ysis 
d uri n g t he treat me nt peri o d f or t he c o nti n u o us meas ure me nts f or select e d la b tests.  Alter nati vel y,  
A N C O V A  will be use d if t he M M R M  m o del is n ot a p plica ble  d ue t o  u na v aila bilit y of m ulti ple 
p ost baseli ne meas ur e me nts.  
Detaile d a n al ys es ca n b e f o u n d i n A p pe n di x 7  ( Secti o n 6. 7 ). 
4. 6. 7.  
A d diti o n al S afet y Assess me nts   
4. 6. 7. 1.  
He p atic S afet y   
4. 6. 7. 1. 1.  He p atic F at Fr acti o n   
T he e n d p oi nt  la bele d “perce nt a n d a bs ol ute cha n ge fr o m baseli ne f or M RI he patic fat fracti o n at 
Da y 1 8 0 ,” will be a n al yz e d usi n g t he S A S .  
A N C O V A will be use d f or t he a nal ysis of b ot h perce nt a n d a bs ol ute c ha n ge.  
4. 6. 7. 1. 2.  He p atic Dis or ders   
T he c o u nts a n d perce nt a ges of partici pa nts wit h T E , p ote ntiall y dr u g -relate d he patic dis or ders, 
will be s u m mariz e d b y tr eat me nt usi n g t he M e d D R A P Ts. Detaile d searc h criteria ca n be f o u n d 
i n A p pe n di x 6 ( Secti o n 6. 6 ) 
A p pr o ve d o n 0 2 J u n 2 0 2 3 G M T


C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 5  
4. 6. 7. 1. 3.  Liver e nzy m e s  
He patic la bs i ncl u de ala ni ne a mi n otra nsferase ( A L T), as part ate a mi n otra nsferase ( A S T), t otal 
bilir u bi n ( T B L), direct bilir u bi n ( D B L), ser u m al k ali ne p h os p hatase ( A L P), i nter nati o nal 
n or malize d rati o (I N R), a n d ga m ma -gl uta m yltra nsferas e ( G G T). W he n crit eria  are met f or 
he patic e v al uati o ns, i n vesti gat ors will c o n d uct cl ose m o nit ori n g of he p atic s y m pt o ms a n d li ver 
tests, perf or m a c o m pre h e nsi ve e val uati o n f or alter nati ve ca us es of a b n or mal li ver tests, a n d 
c o m plete f oll o w -u p he p atic safet y e le ctr o nic case re p ort f or ms (eC R F s). 
Ta ble E Z C B. 4 .5  d escri bes t he pla n ne d s u m mar y ta bles relate d t o he patic safet y.  
 
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 6  
T a bl e E Z C B. 4 .5  
S u m m ar y  T a bl e s  a n d  Fi g ur e s R el at e d t o H e p ati c S af et y   
A n al ysis  
P o p ul ati o n or A n al ysis 
Set   
A b n or mal P ost baseli ne Cate g ories –  He p atic Safet y P ara meters  
A L T  
 
T he n u m ber a n d perce nta ge of partici pa nts wit h a meas ure me nt greater t ha n or e q ual t o 1 X , 3 X, 5 X, 1 0 X, a n d 2 0 X t he 
perf or mi n g la b U L N d uri n g t he treat me nt peri o d f or all partici pa nts wit h a p ost baseli ne val ue.  
A S T  
 
T he n u m ber a n d perce nta ge of partici pa nts wit h a meas ure me nt greater t ha n or e q ual t o 1 X, 3 X, 5 X, 1 0 X, a n d 2 0 X  t he 
perf or mi n g la b U L N d uri n g t he treat me nt peri o d f or all partici pa nts wit h a p ost baseli ne val ue.  
A L P  
 
T he n u m ber a n d perce nta ge of partici pa nts wit h a meas ure me nt greater t ha n or e q ual t o 2 X a n d 3 X  t he perf or mi n g la b U L N 
d uri n g t he treat me nt p eri o d will be s u m marize d f or all partici pa nts wit h a p ost baseli ne.  
T B L  
 
T he n u m ber a n d perce nta ge of partici pa nts wit h a meas ure me nt greater t ha n or e q ual t o 2 X, 5 X , a n d 8 X  t he perf or mi n g l a b 
U L N d uri n g t he treat me nt p eri o d will be s u m marize d f or all partici pa nts wit h a p ost baseli ne val ue.  
D B L  
 
T he n u m ber a n d perce nta ge of partici pa nts wit h a meas ure me nt greater t ha n or e q ual t o 2 X a n d 5 X  t he perf or mi n g la b U L N 
d uri n g t he treat me nt p eri o d will be s u m marize d f or all partici pa nts wit h a p ost baseli ne val ue.  
G G T  
 
T he n u m ber a n d perce nta ge of partici pa nts wit h a meas ure me nt greater t ha n or e q ual t o 2 X  t he perf or mi n g la b U L N d uri n g 
t he treat me nt p eri o d will b e s u m marize d f or all partici pa nts wit h a p ost baseli ne val ue. 
S A S  
 
He p at ocell ular Dr u g -I n d uce d Li ver I nj ur y Scree ni n g Pl ot ( T B L vs A L T or A S T) 
S A S   
He p at ocell ular Dr u g -I n d uce d Li ver I nj ur y Scree ni ng T a ble  
S A S   
C h olestatic Dr u g -I n d uce d Li ver I nj ur y Scree ni n g Pl ot ( T B L vs A L P)  
S A S   
C h olestatic Dr u g -I n d uce d Li ver I nj ur y Scree ni n g T a ble  
S A S   
P artici pa nt  pr ofiles will be create d f or partici pa nts meeti n g criteria f or a c o m pre he nsi ve he patic e val uati o n (as defi ne d i n t he 
pr ot oc ol).  
S A S   
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 7  
A n al ysis  
P o p ul ati o n or A n al ysis 
Set   
P artici pa nt  pr ofiles will i ncl u d e  de m o gra p hics, dis p ositi o n, i nf or mati o n c ollecte d o n t he he patic  safet y C R Fs ( w here a p plica ble) a n d 
a dis pla y of st u d y dr u g e x p os ure, a d verse e ve nts, me dicati o ns, bl o o d press ure, heart rate, a n d t he li ver -relate d meas ure me nts o ver 
ti me. 
A b bre viati o ns: 1 X = o ne ti me t he U L N; 2 X = t w o ti mes t he U L N; 3 X = t hree ti mes t he U L N; 4 X = f o ur ti mes t he U L N; 5 X = fi ve ti mes t he U L N; 1 0 X = te n 
ti mes t he U L N; 2 0 X = t we nt y ti mes t he U L N; A L P = al kali ne  p h os p hatase ; A L T = ala ni ne a mi n otra nsferase ; A S T = as partate a mi n otra nsferase ; C R F = case 
re p ort f or m; D B L = direct bilir u bi n ; F A S = f ull a nal ysis set; G G T = ga m ma -gl uta m yl tra nsferase ; T B L = t otal bilir u bi n; U L N = u p per li mit of n or mal . 
 
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 8  
Pla n ne d a n d u n pla n ne d meas ure me nts will be i ncl u de d  i n t he a nal yses liste d i n Ta ble E Z C B. 4 .5 . 
T he meas ur e me nts d o n ot nee d t o be ta ke n at t he s a me bl o o d dra w.  T h e m a xi m u m baseli ne will 
be t he ma xi m u m n o n -missi n g o bser vati o n i n t he baseli ne peri o d. T he ma xi m u m val ue will be t he 
ma xi m u m  n o n -missi n g val ue fr o m t he p ost bas eli ne peri o d.  
T he pri mar y p ur p os e of t he scree ni n g pl ots is t o i de ntif y p artici pa nts w h ose data warra nt f urt her 
re vie w. F or t hes e pl ots, s y m b ols will be use d t o i n dicate t he ra n d o mize d treat me nt. 
F or i n di vi d ual partici pa n ts of i nterest, partici pa nt pr ofiles will be re vie we d. T his  re vie w will 
i ncl u de w hic h treat me nt t he partici pa nt was ta ki n g o ver ti me, t he c ha n ges i n he patic la bs o ver 
ti me, a n d t he te m p oral ass ociati o n wit h p ote ntial ca uses. T he re vie w of partici pa nt pr ofiles will 
als o i ncl u de t he i de ntificati o n of a n y p ote ntial H y’s la w cas e or p ote ntial c h olestatic li ver i nj ur y 
case t hat ma y  h a ve bee n misse d b y f oc usi n g o nl y o n t he ma xi m u m val ues w he n deter mi ni n g 3 0 -
da y ti me ass ociati o ns . 
4. 6. 7. 1. 4.  G all bl a d der a n d bili ary tr act dis or ders   
T he c o u nts a n d perce nt a ges of partici pa nts wit h tr eat me nt-e mer ge nt,  p ote ntiall y dr u g -relate d 
gall bla d d er a n d biliar y tr act dis or ders will be s u m marize d b y tr eat me nt usi n g t he M e d D R A P Ts. 
Detaile d searc h criteria ca n be f o u n d i n A p p e n di x 6 ( Secti o n 6. 6 ). 
4. 6. 7. 2.  
H y perse nsiti vit y E ve nts   
H y p erse nsiti vit y reacti o ns a n d relate d i nf or mati o n re p orte d i n t he e C R F will be liste d a n d 
s u m marize d b y treat me nt. 
T w o mai n a nal yses will be  perf or me d:  
 P ote ntial I m me diate H y p erse nsiti vit y : anal ysis of T E A Es occ urri n g fr o m t he start of 
st u d y dr u g a d mi nistrati o n u p t o 2 4 h o urs after t he e n d of st u d y dr u g a d mi nistrati o n. F or 
e ve nts wit h o ut t he h y p erse nsiti vit y e C R F, o nl y d ate ( n o ti me) i nf or mati o n is c ollecte d, 
a n d a n y e v e nts occ urri n g o n t he sa me date as t he st u d y dr u g i njecti o n dat e will be 
i ncl u de d. 
 P ote ntial N o n -I m me di ate H y p erse nsiti vit y: an al ysis of T E A Es occ urri n g m ore t ha n 2 4 
h o urs after t h e e n d of st u d y dr u g a d mi nistrati o n b ut pri or t o s u bse q ue nt st u d y dr u g 
a d mi nistrati o n.  
S u m maries of a ll p ote ntial h y p erse nsiti vit y reacti o ns will be ge n erat e d b y P T wit h decreasi n g 
fre q ue n c y b y treat me nt. T he A E data base will be searc h e d usi n g pre d efi ne d Sta n dar dize d 
Me d D R A Q ueri es  (S M Qs ) t o i de ntif y e v e nts c o nsiste nt wit h h y p erse nsiti vit y e v e nts. Detaile d 
searc h criteri a ca n b e f o u n d i n A p pe n di x 6 ( Secti o n 6. 6 ). 
4. 6. 7. 3.  
I njecti o n Site Re acti o ns  
I nje cti o n site reacti o ns, i nci de nce, a n d rel ate d i nf or mati o n re p orte d i n t he e C R F will be 
s u m marize d b y treat me nt. I nf or mati o n t o be s u m marize d i ncl u des t he ti mi n g of t he reacti o n  
relati ve t o st u d y dr u g a d mi nistrati o n a n d c haracteristics of t he i njecti o n site reacti o n. S uc h 
c haracteristics i ncl u de  er yt he ma, i n d urati o n, pai n, pr urit us , a n d e de ma.  
P ote ntial i njecti o n site reacti o ns will be searc he d b y pre defi n e d Me d D R A Hi g h Le v el Ter ms 
(H L Ts ) of i njecti o n site reacti o ns, a d mi nistrati o n site reacti o ns, a n d i nf usi o n -relate d reacti o ns. 
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 2 9  
Detaile d searc hi n g criteri a f or i njecti o n site reacti o n e ve nts ca n b e f o u n d i n A p pe n di x 6  ( Secti o n 
6. 6 ). T he P T will be use d f or t he s u m mar y b y treat me nt wit hi n eac h H L T cate g or y.  
4. 6. 7. 4.  
M aj or A d ve rse C a r di o v asc ul ar E ve nts   
Deat h a n d no nfatal car di o vasc ular A Es ( N C A Es) will be a dj u dicate d b y a c o m mittee of 
p h ysicia ns e xter nal t o Lill y wit h car di ol o g y e x pertise. T his c o m mittee will be bli n de d t o 
treat me nt assi g n me nt.  
T he N C A Es t o be a dj u di cate d i ncl u de  
 m y ocar dial i nfarcti o n  
 car dio ge nic s h o c k d ue t o m y ocar dial i nfarcti o n  
 h os pitaliz ati o n f or u nsta ble a n gi na  
 h os pitaliz ati o n f or heart fail ure  
 c or o nar y i nter ve nti o ns (s uc h as c or o nar y arter y b y pass graft or p erc ut a ne o us c or o nar y 
i nter ve nti o n)  
 res uscitate d s u d de n d eat h, a n d  
 cere br o vasc ul ar e v e nts, i ncl u di n g cere br o vasc ul ar acci de nt (str o k e) a n d tra nsie nt 
isc he mic attac k.  
T he c o u nts a n d perce nt a ges of partici pa nts wit h a dj u dicate d N C A Es  ma y be s u m marize d b y 
treat me nt. 
I n a d diti o n, N C A Es  re p orte d b y i n v esti gat or ma y als o be s u m marize d. Deat h re p orte d b y 
i n vesti gat or ma y b e liste d i n a se parate ta ble. 
A listi n g of partici pa nts r e p orti n g N C A Es , eit her re p orte d b y a n i n vesti gat or or i de ntifie d b y t he 
cli nical e n d p oi nt c o m mittee ( C E C ), will be pr o vi d e d. T h is listi n g will i ncl u de treat me nt, 
partici pa nt i de ntificati o n i ncl u di n g t he site n u m ber, date of e v e nt, t y p e of e v e nt as re p ort e d b y 
t he i n vesti gat or, t y p e of e ve nt as a dj u dicate d b y t h e C E C, ti me fr o m first d ose of st u d y dr u g t o 
t he e ve nt, a n d ti me fr o m last d ose t o t he e ve nt (if partici pa nt has disc o nti n ue d st u d y dr u g pri or t o 
t he e ve nt). 
4. 7.  
Ot her A n al yses   
S u b gr o u p a n al ys es of t he pri mar y e n d p oi nt will be c o n d ucte d  t o assess t he c o nsiste nc y of t he 
i nter ve nti o n effect a cr oss t he f oll o wi n g s u b gr o u ps:  
 age gr o u p: u n der 6 5  years  v ersu s 6 5 years a n d o ver 
 race  
 se x : fe male vers us male 
 et h nicit y 
 B MI ( k g/ m 2 ) gr o u p: less t ha n 3 0 v ers us 3 0 or hi g h er , a n d less t ha n 3 5 v ers u s 3 5 or hi g her  
 Visit 1 T G le vel less t ha n 2 5 0 m g/ d L v ers us 2 5 0 m g/ d L  or hi g her  
 Visit 1 T G a n d L D L-C le vels: T G 2 5 0 m g/ d L or hi g her  a n d L D L-C 1 0 0 m g/ d L  or hi g her,  
v ers us T G less t ha n 2 5 0 m g/ d L a n d L D L -C l ess t ha n1 0 0 m g/ d L , a n d 
 d ia betic vs n o n -dia bet ic. 
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 3 0  
F or eac h s u b gr o u p a nal ysis, 2 m o dels will be c o n d ucte d:  
 M M R M m o del: co n d uct M M R M m o del as descri be d i n Secti o n 4. 3. 2  o n t he s u b gr o u p 
o nl y , a n d 
 M M R M m o del  wit h i nteracti o n s: t he M M R M m o del as descri b e d i n Secti o n 4. 3. 2 , 
a d di n g i nteracti o ns bet w ee n s u b gr o u p a n d visit, b et wee n s u b gr o u p a n d treat me nt , a n d 
bet wee n s u b gr o u p, treat me nt a n d visit as fi x e d e ffects.  
S e parate M M R Ms ma y  b e c o n d ucte d o n p artici pa nts meeti n g t he i ncl usi o n/e xcl usi o n criteria f or 
t he St u d y E Z C B pr ot o c ol b ot h bef ore a n d after a m e n d me nt (e): Visit 1 li pi d le vels of  T G greater 
t ha n 2 0 0 m g/ d L a n d L D L -C greater t ha n 1 0 0 m g/ d L v ers us T G greater t ha n 1 5 0 m g/ d L a n d L D L 
greater t ha n 7 0 m g/ d L a n d n o n -H D L -C greater t h a n 1 3 0 m g/ d L . If less t ha n 1 0 % of partici pa nts 
differ bet w ee n t hes e t w o s u b gr o u ps , t his a nal ysis will n ot be pr o d uce d. 
If t he n u m ber of partici p a nts is t o o s mall (less t ha n 1 0 %) withi n a s u b gr o u p, t he n t he s u b gr o u p 
cate g ories m a y be re defi ne d pri or t o u n bli n di n g t he st u d y.  A d diti o nal s u b gr o u p a nal yses ma y 
als o be perf or me d.  
F or t he p ur p os es of t he s u b gr o u p a nal ysis, dia beti c stat us will be defi ne d usi n g t he criteria 
descri be d i n A p p e n di x 8 ( Secti o n  6. 8 ). 
S u b gr o u p a n al ys es ma y be d o ne f or t h e J a pa nese p o p ulati o n t o s u p p ort l ocal re g ulat or y 
i nteracti o ns. 
4. 8.  
I nteri m A n al ys es  
A first -pla n ne d i nteri m a nal ysis ma y be c o n d ucte d w he n at least 5 0 % of partici pa nts c o m plete 
Da y 1 2 0 ( Visit 7) or disc o nti n ue treat me nt. T here ma y b e 2 m ore i nteri m a nal yses aft er t he first 
i nteri m a nal ysis a n d b ef ore fi nal a n al ysis ( 1 0 0 % of patie nts c o m plete 1 8 0 da ys of st u d y or 
disc o nti n ue treat me nt). T hese 3 i nteri m a nal yses will be f or t he p ur p ose of i nter nal pla n ni n g a n d 
decisi o n ma ki n g a n d ma y ass ess safet y, P K, or efficac y  meas ures . 
If a n u n pla n n e d i nteri m a nal ysis is dee me d necessar y f or reas o ns ot her t ha n a safet y c o ncer n, t he 
St u d y E Z C B pr ot oc ol m ust be a me n de d.  
A n i nteri m assess me nt c o m mittee (I A C) will be f or me d t o re vie w t h e i nteri m a nal yses f or 
t otalit y of data i ncl udi n g t he safet y a n d effi cac y re p orts i n a n u n bli n de d ma n ner . 
T he I A C will be f ull y i n de pe n de nt fr o m t he st u d y t ea m a n d will i ncl u de, at a mi ni m u m, a Lill y 
me dical p h ysi cia n a n d a statisticia n. Details a b o ut I A C me m bers hi p, p ur p ose, res p o nsi bilities, 
a n d o perati o n will be des cri be d i n a n I A C c hart er, w hic h will be a p pr o ve d pri or t o t he first 
u n bli n di n g . 
Details o n t he ti mi n g of t he i nteri m a nal yses, o perati o nal s u p p ort, a n d u n bli n di n g will be 
s pecifie d i n t he I A C c harter a n d i n t he St u d y E Z C B u n bli n di n g pla n . Si nce t he e n d p oi nts f or 
i nteri m a nal ysis are a s u bset of t he e n d p oi nts i n Secti o n 1. 1 , t he a nal ysis met h o ds f or t hese 
e n d p oi nts s h o ul d be c o nsiste nt wit h t h ose met h o ds descri be d i n t his S A P . T he ti me p oi nts of at 
w hic h cert ai n e n d p oi nts are ass esse d ma y b e a me n de d  t o reflect data a v aila bilit y at t he i nteri m. 
S uc h c ha n ges will be s pecifie d i n t he I A C c h arter.  
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L Y 3 5 6 1 7 7 4  
P A G E 3 1  
I nf or mati o n t hat ma y u n bli n d S t u d y E Z C B d uri n g t he a nal yses will n ot be re p orte d t o st u d y sites 
or bli n de d st u d y te a m me m bers bef ore t he st u d y h as bee n u n bli n de d u ntil fi nal data base l o c k. 
St u d y sites will recei ve i nf or mati o n a b o ut i nteri m res ults o nl y if dee me d n ecessar y f or t he s afet y 
of t he partici pa nts. S t u d y E Z C B  will n ot be st o p pe d base d o n t he s u peri orit y of L Y 3 5 6 1 7 7 4 
vers us place b o. T heref ore, t here will be n o i nfl ati o n of t he t y p e I err or rate a n d n o nee d t o 
e m pl o y a n al p ha s pe n di n g f u ncti o n or m ulti plici t y a dj ust me nt.  
4. 9.  
C h a n ges t o Pr ot o c ol-Pl a n ne d A n al yses   
T he descri pti o n of t he E A S was a me n de d t o e x cl u de  partici pa nts w h o e x perie nce d  per m a ne nt 
disc o nti n uati o n of i nter ve nti o n , i nitiati o n of e x cl u de d me dicati o ns ta ke n d uri n g t he st u d y, a n d 
ne w i nitiati o n of a n y li pi d -l o weri n g dr u g re q uire d t o be o n a sta ble re gi me n pri or t o treat me nt per 
t he St u d y E Z C B  pr ot o c ol i ncl usi o n criteria . I n t he St u d y E Z C B pr ot oc ol , t h e E A S was des cri be d 
as o nl y e x cl u di n g m eas ur e me nts base d o n per ma n e nt disc o nti n uati o n of i nter ve nti o n . T his 
c ha n ge is i nte n de d t o ali g n t he a nal yses bas e d o n t he E A S wit h t he descri pti o n of t he pri mar y 
esti ma n d, base d o n t he h y p ot hetic al strate g y.  
F or t he e x pl orat or y a n al ysi s of ti me-a vera ge d e n d p oi nts, t he da ys of ti me -a vera gi n g ha v e bee n 
a u g m e nte d fr o m D a y 1 2 0  t o Da y 1 8 0 t o  Da y  3 0  t o Da y 1 8 0 , a n d fr o m Da y  2 1 0  t o Da y 2 7 0 t o 
Da y 1 2 0  t o Da y  2 7 0. T h e p ur p ose of t his c ha n ge is t o ca pt ure a br oa d er  meas ure of effecti ve ness 
o ver ti me t o acc o m p a n y o ur ot her a n al ys es at s pe cific ti me p oi nts.  
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C O N FI D E N TI A L  
J 3 F-M C -E Z C B  Statistical A nal ysis Pla n  Versi o n 1  
L Y 3 5 6 1 7 7 4  
P A G E 3 2  
5.  
S a m ple Size Deter mi n ati o n   
T he sa m ple siz e calc ulati o n is base d o n t he pri mar y efficac y esti ma n d a n d its e n d p oi nt, perce nt 
c ha n ge, fr o m baseli ne at Da y 1 8 0 i n A p o B. 
A p pr o xi matel y 1 7 5 p arti ci pa nts will be ra n d o ml y assi g ne d i n a 2: 1: 2: 2 rati o t o place b o: 
L Y 3 5 6 1 7 7 4 1 0 0 m g: 4 0 0 m g: 8 0 0 m g. Ass u mi n g a  
 dr o p o ut rate, t his res ults i n 
a p pr oxi matel y 2 0 c o m pleters f or t he 1 0 0 m g gr o u p a n d 4 0 c o m pleters p er ar m f or t he rest of t he 
gr o u ps.  
Ass u mi n g a sta n d ar d de viati o n of 1 5 %, a n d a 2 -si de d al p ha le v el of 0. 0 5, t he c o m pleters f or eac h 
treat me nt ar m will pr o vi de great er t ha n 9 9 % p o wer t o detect a  treat me nt differe nce of -3 0 % f or 
t he pri mar y e n d p oi nt. 
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6.  
S u p p orti n g D oc u me nt ati o n   
6. 1.  
A p pe n di x 1: De m o gr a p hic a n d B aseli ne C h ar acteristics   
A listi n g of partici pa nt d e m o gra p hics f or all ra n d o ml y assi g ne d partici pa nts will be pr o vi de d. All 
de m o gra p hic a n d b aseli n e cli nical c haracteristics will be s u m marize d b y tr eat me nt gr o u ps f or all 
ra n d o ml y assi g n e d partici p a nts. 
Baseli ne d e m o gra p hic a n d cli nical c haracteristics of s pecial i nterest i ncl u de b ut are n ot li mite d t o  
 a ge ( years ) 
 se x (fe male, male) 
 race 
 et h nicit y 
 hei g ht ( c m ) 
 wei g ht ( k g ) 
 b o d y mass i n de x ( B MI [k g/ m 2 ])  
 a ge gr o u p (l ess t ha n 6 5 years, 6 5 years  or o ver ) 
 B MI gr o u p ( less t ha n 3 0,  3 0  or great er  a n d less t h a n 3 5, 3 5 or greater ) 
 L D L -C  
 H D L -C  
 V L D L -C  
 T Gs  
 A N G P T L 3  
 n o n -H D L -C  
 A p o B , a n d  
 Visit 1  T G strat u m (less t ha n 2 5 0 m g/ d L, 2 5 0 m g/ d L  or great er ). 
6. 2.  
A p pe n di x 2: Hist oric al Ill nesses a n d Pree xisti n g C o n diti o ns   
T he c o u nt a n d perce nta ges of partici pa nts wit h hist orical ill nesses a n d pree xisti n g c o n diti o ns will 
be s u m mariz e d b y tr eat m e nt gr o u ps usi n g t he M e d D R A P Ts neste d wit hi n S O C s. T he S O Cs will 
be i n al p ha betical or der. C o n diti o ns ( t hat is, P Ts) will be or dere d b y d ecreasi n g fre q ue nc y wit hi n 
t he S O C. T his will be s u m marize d f or all ra n d o ml y assi g ne d p artici pa nts.  
6. 3.  
A p pe n di x 3 : Tre at me nt C o m pli a nce  
Listi n g a n d s u m mar y of pre mat urel y disc o nti n ui n g st u d y treat me nt (i ncl u di n g disc o nti n uati o n 
reas o n) a n d disc o nti n ui n g st u d y will be pr o vi de d b y treat me nt gr o u ps.  
6. 4.  
A p pe n di x 4 : C onc o mit a nt Me dic ati o ns   
C o nc o mita nt me dicati o ns will be s u m marize d b y treat me nt gr o u p. T he p erce nta ges of 
partici pa nts w h o t o o k c o nc o mita nt me dicati o n will be s u m marize d b y treat me nt usi n g P Ts neste d 
wit hi n A nat o mical T hera pe utic C he mical ( A T C) Le v el 3 c o des. T h e c o n c o mita nt me dicati o ns 
will be or dere d b y d ecreasi n g fre q ue nc y wit hi n eac h A T C le vel  i n t he L Y 3 5 6 1 7 7 4 1 0 0  m g 
gr o u p . 
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6. 5.  
A p pe n di x 5: I m p ort a nt Pr ot oc ol De vi ati o ns   
I m p ort a nt pr ot oc ol de viati o ns are i de ntifie d i n t he Trial Iss ues Ma n a ge me nt Pla n. A listi n g a n d 
s u m mar y of i m p orta nt pr ot oc ol de viati o ns b y tr eat me nt gr o u ps will be pr o vi de d at t he e n d of 
S t ud y  E Z C B  f or all ra n d o ml y assi g ne d partici pa nts.  
6. 6.  
A p pe n di x 6: Se arc hi n g Criteri a f or A d diti o n al S afet y Assess me nts   
He p atic Tre at me nt -E mer ge nt A d verse E ve nts  
Treat me nt -e mer ge nt p ote ntiall y dr u g -relate d h e patic dis or ders will be s u m marize d b y tr eat me nt 
usi n g t he Me d D R A P Ts c o ntai ne d i n a n y of t he S M Qs  
 Br oa d a n d narr o w ter ms i n t he Li ver -relate d i n vesti gati o ns, si g ns a n d s y m pt o ms S M Q 
( 2 0 0 0 0 0 0 8) 
 Br oa d a n d narr o w ter ms i n t he C h olest asis a n d ja u n dice of he patic ori gi n S M Q ( 2 0 0 0 0 0 0 9)  
 Br oa d a n d narr o w ter ms i n t he He patitis n o n -i nfecti o ns S M Q ( 2 0 0 0 0 0 1 0) 
 Br oa d a n d narr o w ter ms i n t he He patic fail ure, fi br osis a n d cirr h osis a n d ot h er li ver 
da ma ge S M Q ( 2 0 0 0 0 0 1 3) , a n d 
 Narr o w t er ms i n t he Li v er -relat e d c oa g ul ati o n a n d blee di n g dist ur ba nces S M Q 
( 2 0 0 0 0 0 1 5). 
G all bl a d der a n d bili ar y tr act dis or ders  
Treat me nt -e mer ge nt gall bla d der a n d biliar y tr act dis or ders  will be s u m marize d b y treat me nt 
usi n g t he Me d D R A P Ts c o ntai ne d i n a n y of t he S M Qs  
 Narr o w P Ts i n Gall bla d d er rel ate d dis or ders S M Q ( 2 0 0 0 0 1 2 4)  
 Narr o w P Ts i n Biliar y tract dis or ders S M Q ( 2 0 0 0 0 1 2 5) , a n d  
 
Narr o w P Ts i n Gallst o ne relate d dis or ders S M Q ( 2 0 0 0 0 1 2 7).  
I njecti o n Site Re acti o ns 
Treat me nt -e mer ge nt i nje cti o n site reacti o n s will be s u m marize d b y tr eat me nt usi n g t he Me d D R A 
P T i n a n y of t he f oll o wi n g  Me d D R A H L T s 
 I nje cti o n site reacti o n 
 A d mi nistrati o n site reacti o n , a n d 
 I nf usi o n site reacti o ns . 
H y perse nsiti vit y E ve nts  
T he h y p erse nsiti vit y T E A E are c haracterize d as f oll o ws  
 A na p h yl actic reacti o n S M Q ( 2 0 0 0 0 0 2 1; narr o w, al g orit h m per S M Q g ui d e, a n d br oa d)  
 H y p erse nsiti vit y S M Q ( 2 0 0 0 0 2 1 4; narr o w a n d br oa d)  
 A n gi oe d e ma S M Q ( 2 0 0 0 0 0 2 4; narr o w a n d br oa d) , a n d 
 E ve nt ma ps t o P T of I nj ecti o n relate d reacti o n ( 1 0 0 7 1 1 5 2).  
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Usi n g t hese f o ur S M Qs , the n u m ber a n d p erce nta ge of partici p a nts  w h o e x perie nce d a T E A E f or 
t he f oll o wi n g will be a n al yz e d f or eac h of t he t w o  st u d y i nter ve nti o n ti me peri o ds ( Da y 0 t o D a y 
9 0 a n d Da y 9 0 t o eit her Da y 1 8 0 or D a y 2 7 0 de p e n di n g o n s afet y f oll o w -u p ): 
 an y n arr o w or al g orit h mi c ter m fr o m a n y o n e of t h e 4 i n dicate d S M Qs (t hat is,  c o m bi ne d 
searc h acr oss n arr o w a n d al g orit h mic p orti o ns of all 4 S M Qs) 
 an y n arr o w sc o pe t er m wit hi n eac h S M Q, se paratel y (t hat is, narr o w S M Q s earc h) , a n d 
 an y t er m wit hi n eac h S M Q, separatel y (t hat is, br oa d S M Q searc h).  
 
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P A G E 3 6  
6. 7.  
A p pe n di x 7 : Cli nic al L a b or at or y E v al u ati o n   
T a bl e 6 .1  T a bl e s a n d Fi g ur e s Pr o d u c e d t o S u p p ort Cli ni c al L a b or at or y E v al u ati o n s   
A n al ysis T y pe  
A n al ysis Det ails  
P o p ul ati o n/ A n al ysis 
Set  
B o x pl ots a n d mea n/ S D pl ots 
f or o bser ve d val ues b y visit 
I ncl u des partici pa nts w h o ha ve b ot h a baseli ne a n d at least 1 p ost baseli ne meas ure me nt fr o m a 
pla n ne d visit.  
 
U n pla n ne d meas ure me nts will be e xcl u de d.  
 
Last baseli ne will be use d.  
 
Ori gi nal -scale data will be use d. 
 
B ot h SI a n d c o n ve nti o nal u nits will be pr o vi de d i n t he a xis wit hi n a si n gle pl ot.  
 
N o i nfere ntial statistics.  
 
See als o: Fi g ure 6. 1 fr o m t he A nal yses a n d dis pla ys A ss ociate d wit h L a b orat or y A nal yte 
M eas ure me nts i n P hase 2 -4 C li nical T rials a n d Inte grate d S u b missi o n D oc u me nts –  U p date t o 
R ec o m me n dati o ns  w hite pa per a.  
F A S  
B o x pl ots a n d mea n/ S D pl ots 
f or c ha n ge fr o m baseli ne val ues 
b y visit  
I ncl u des partici pa nts w h o ha ve b ot h a baseli ne a n d at least 1 p ost baseli ne meas ure me nt fr o m a 
pla n ne d visit.  
 
U n pla n ne d meas ure me nts will be e xcl u de d.  
 
Last baseli ne will be use d.  
 
N o i nfere ntial statistics.  
 
See als o: Fi g ure 6. 2 fr o m t he A nal yses a n d Dis pla ys Ass oci ate d wit h La b orat or y A nal yte 
Meas ure me nts i n P hase 2 -4 Cli nical Trials a n d I nte grate d S u b missi o n D oc u me nts –  U p date t o 
Rec o m me n dati o ns  w hite pa per a. 
F A S  
M a xi m u m, mi ni m u m, a n d last 
o bser ve d a n d c ha n ge val ues  
I ncl u des all partici pa nts w h o ha ve b ot h a baseli ne a n d at least 1  p ost baseli ne meas ure me nt . 
 
F A S  
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A n al ysis T y pe  
A n al ysis Det ails  
P o p ul ati o n/ A n al ysis 
Set  
T he f oll o wi n g will be s u m marize d:  
o  
last baseli ne, last p ost baseli ne, c ha n ge fr o m last baseli ne t o l ast p ost baseli ne (last 
p ost baseli ne mi n us last baseli ne)  
o  
mi ni m u m baseli ne, mi ni m u m p ost baseli ne, c ha n ge fr o m mi ni m u m baseli ne t o t he 
mi ni m u m p ost baseli ne ( mi ni m u m p ost baseli ne mi n us mi ni m u m baseli ne), a n d  
o  
ma xi m u m baseli ne, ma xi m u m p ost baseli ne, c ha n ge fr o m ma x i m u m baseli ne t o t he 
ma xi m u m p ost baseli ne ( ma xi m u m p ost baseli ne mi n us ma xi m u m baseli ne)  
P -val ues usi n g t he M M R M or A N C O V A m o del s will be i ncl u de d.  
 
See als o: T a ble 6. 2 fr o m t he A nal yses a n d Dis pla ys Ass ociat e d wit h La b orat or y A nal yte 
Meas ure me nts i n P hase 2 -4 Cli nical Trials a n d I nte grate d S u b missi o n D oc u me nts –  U p date t o 
Rec o m me n dati o ns f or La bs w hite pa per a.  
P artici pa nts wit h ele vate d or 
l o w val ues meeti n g s pecifie d 
le vels 
E xcl u des a nal ytes c ollecte d q ualitati vel y.  
 
Defi niti o ns pr o vi de d i n T a ble 5 9 a n d 6 0 fr o m F D A’s Sta n dar d Safet y T a bles a n d Fi g ures I nte grate d 
G ui de will be use d f or t he n u merat or b . . 
 
I ncl u des partici pa nts wit h at le ast 1 p ost baseli ne meas ure me nt. 
 
F or i nitial c o ntr olle d a nal ysis sets, ma xi m u m baseli ne is use d f or ele vate d assess me n ts a n d 
mi ni m u m baseli ne is use d f or l o w assess me nts . 
 
F or L Y -treate d a nal ysis sets (a ll partici pa nts recei vi n g at least 1 d ose of  L Y 3 5 6 1 7 7 4 ), partici pa nts 
ra n d o ml y assi g ne d t o place b o or acti ve c o m parat or i n t he i nitial peri o d, last baseli ne is use d f or a ny 
c ha n ge calc ulati o ns . 
 
F or c o ntr olle d a nal ysis sets, st atistical c o m paris o ns ( usi n g met h o ds descri be d i n Secti o n  4. 3. 2 ) will 
be i ncl u de d.  
 
See T a ble 2 4 fr o m F D A’s Sta n dar d Safet y T a bles a n d Fi g ur es I nte grate d G ui de ( F D A 2 0 2 2 ). 
F A S  
Listi n g of a b n or mal la b orat or y 
fi n di n gs 
I ncl u des la b orat or y a nal ytes c ollecte d q ua ntitati vel y ( hi g h or l o w d uri n g p ost baseli ne usi n g Le vel 2 
defi niti o ns) a n d q ualitati vel y (a b n or mal d uri n g p ost baseli ne) . 
 
F A S  
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P A G E 3 8  
A n al ysis T y pe  
A n al ysis Det ails  
P o p ul ati o n/ A n al ysis 
Set  
I ncl u des partici pa nt i de ntificati o n, treat me nt gr o u p, la b orat or y a nal yte c ollecti o n da y (t hat is, da ys 
fr o m start of st u d y i nter ve nti o n), a nal yte na me, a n d a nal yte fi n di n g.  
A b bre viati o ns: A N C O V A = a nal ysis of c o varia nce; F A S = f ull a nal ysis set; M M R M = mi xe d m o del re peate d meas ures ; S D = sta n dar d de viati o n. 
a [ P H U S E]. Safet y A nal ytics W or ki n g Gr o u p. A nal yses a n d dis pla ys ass ociate d wit h la b orat or y a nal yte meas ure me nts i n p hase 2 -4 cli nical trials a n d i nte grate d 
s u b missi o n d oc u me nts –  u p date t o rec o m me n dati o ns. Accesse d Marc h 0 5, 2 0 2 3. htt ps:// p h use.s 3.e u -ce ntral -
1.a maz o na ws.c o m/ Deli vera bles/ Safet y + A nal ytics/ W P 0 6 8. p df  
b  [F D A] U ni te d States F o o d a n d Dr u g A d mi nistrati o n. Sta n dar d safet y ta bles a n d fi g ures: i nt e grate d g ui de. A u g ust 2 0 2 2. Accesse d Ma y 3 1, 2 0 2 3. 
htt ps:// d o w nl oa ds.re g ulati o ns. g o v/ F D A -2 0 2 2 -N -1 9 6 1 -0 0 4 6/attac h me nt _ 1. p df  
 
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6. 8.  
A p pe n di x 8: Defi niti o n of D i a betic S t at us  
F or t he p ur p os es of t he s u b gr o u p a nal ysis  o n dia betic stat us,  partici pa nts will be defi ne d as 
dia betic if , pri or t o bei n g ra n d o ml y assi g n e d , t he y p ossess A N Y of 
 ba seli ne he m o gl o bi n A 1c le vels great er t ha n 6. 5 %  
 c o nc o mita nt me dicati o ns  classifie d as a dr u g us e d i n di a betes  acc or di n g t o t he 
A nat o mical T hera pe utic C he mical ( A T C) le vel 2  c o de A 1 0.  
 me dical hist or y classifie d u n der t he  Me d D R A  P T Di a betes Mellit u s, or 
 m e dical hist or y classifie d u n der t he Me d D R A  L L T Di a betes Mellit u s. 
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7.  
Refere nces   
Q u Y, Li u Z, F u H , et al. M o deli n g t he i m pact of pre pla n ne d d os e titrati o n o n dela ye d res p o nse. 
J Bi op h ar m St at . 2 0 1 9; 2 9( 2): 2 8 7-3 0 5. htt ps:// d oi. or g/ 1 0. 1 0 8 0/ 1 0 5 4 3 4 0 6. 2 0 1 8. 1 5 3 5 4 9 9  
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Si g nat ure Pa ge f or V V- C LI N- 0 7 2 1 4 5 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 0 7 2 1 4 5 v 1. 0
A p pr o val
0 2-J u n- 2 0 2 3 1 1: 4 4: 1 2 G M T + 0 0 0 0
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P P D