A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of LY3540378 in Adults With Worsening Chronic Heart Failure With Preserved Ejection Fraction (HFpEF)
Phase: PHASE2
Conditions: Heart Failure, Heart Failure With Preserved Ejection Fraction
Sponsor: Eli Lilly and Company

Protocol A
 ( ) 
 
NCT
Approval Date: 9-
-20

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J3E-MC-EZDB(b) 
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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 LY3540378, 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 LY3540378 in Adults with Worsening Chronic Heart 
Failure with Preserved Ejection Fraction (HFpEF) 
Protocol Number: J3E-MC-EZDB 
Amendment Number: b 
Compound: LY3540378 
Brief Title: Efficacy and Safety of LY3540378 in Adults with Worsening Chronic Heart Failure 
with Preserved Ejection Fraction 
Study Phase: 2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA46285 
Regulatory Agency Identifier Numbers: 
IND: 152593 
EudraCT Number: 2022-000780-48 
EU CT Number: 2023-505902-40-00 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-119494

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J3E-MC-EZDB(b) 
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Medical monitor Name and Contact Information will be provided separately. 
 
 

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J3E-MC-EZDB(b) 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY
Document 
Date
Amendment a 
01-Jun-2023
Original Protocol
07-Jun-2022
Amendment [b]  
The amendment is considered to be substantial because it is likely to have a significant impact on 
the  
 safety or the rights of the study participants, and 
 the quality or safety of any investigational medicinal product used in the 
study. 
Overall Rationale for the Amendment: 
The overall rationale for this amendment is to  
 update the language for the hepatic monitoring criteria 
 clarify sample size, and 
 better assess the outcomes of the 50 mg and 100 mg study arms. 
Section # and Name
Description of Change
Brief Rationale 
Throughout 
Revised the number of 
6  
To account for the participant drop 
off rate that is higher than initially 
planned 
Revised the randomization ratio to 
 
To better assess the outcomes of 
the 50 mg and 100 mg study arms  
Synopsis 
Study Population subsection: 
Updated criteria 
Updated to align with clarification 
to inclusion criteria 1, 2, and 3 in 
Section 5.1. 
Synopsis 
3. Objectives, Endpoints, and 
Estimands 
8.1.2. Other Efficacy Assessments 
Revised the equation to be used 
for calculating eGFR from 
creatinine and cystatin 
CKD-EPI Creatinine-Cystatin 
 
Clarification 
1.3. Schedule of Activities (SoA) 
Screening: 
Added statement that sample 
collections for the local and 
central laboratories and the ECG 
test should all be done on the same 
day. Other screening procedures, 
for example, ECHO may be 
conducted on another day. 
Telehealth visits: 

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J3E-MC-EZDB(b) 
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Section # and Name
Description of Change
Brief Rationale 
 
Visits 1 through 16 table 
Laboratory Tests and Sample 
Collections row: Added statement 
on reinforcing the importance of 
collecting BNP, NT-proBNP, and 
eGFR sample for both central and 
local laboratory testing on the 
same day 
Visits 
, ED, and 
Follow-Up table
Added important note to reiterate 
that from 
 
 
 
section:
 Administer study intervention 
 Updated the notes to administer 
study intervention 
2.2. Background 
Clinical Study EZDA preliminary 
results subsection: 
an 
 
Study EZDA has been completed 
5.1. Inclusion Criteria 
 
Criterion 1: 
Added indication and deleted the 
i
 
Clarification 
Criterion 2 has been deleted 
Clarification and requested by 
investigators 
Criterion 3B: 
 
Clarification 
Criterion 3: 
Revised the IV requirement of the 
bolus doses of IV diuretics at that 
 
Clarification and requested by 
investigators 
 
Criterion 6B: 
Revised definition of treatment 
 
To align with the revisions made 
to criterion 3 
Criterion 8: 
Added unit for measurement of 
eGFR: mL/min/1.73 m2 
For editorial consistency 

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J3E-MC-EZDB(b) 
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Section # and Name
Description of Change
Brief Rationale 
Criterion 9: 
 Revised the criterion to A  and 
B  
 
not need to be at a stable 
 
Clarification and requested by 
investigators 
5.2. Exclusion Criteria 
Criterion 26: Specified that a 
participant is considered eligible if 
subsequently the hemoglobin is 
 g/dL before V2 
(randomization) 
Clarification 
Criterion 38: 
classification for evidence of 
hepatic insufficiency 
To comply with updated guidance 
from internal liver safety 
monitoring committee to enhance 
monitoring 
New criterion added: 48 
De novo (first occurrence or 
diagnosis) HFpEF is not permitted 
Clarification and requested by 
investigators 
5.5. Criteria for Temporarily 
Delaying Enrollment, 
Randomization, or Administration 
of Study Intervention of a 
Participant 
Administration of Study 
heading 
To clarify the criteria applicable 
for the study 
6.3. Measures to Minimize Bias: 
Randomization and Blinding 
Updated section with the revised 
randomization ratio  
To better assess the outcomes of 
the 50 mg and 100 mg study arms. 
6.8. Concomitant Therapy 
Added language from the 2022 
AHA/ACC/HFSA Guideline, 
where SGLT-2i is designated a 
Class 2A indication in decreasing 
HF hospitalizations and 
cardiovascular mortality in HFpEF 
participants 
Clarification 
7.1.1. Hepatic Criteria for Study 
Intervention Interruption or 
Discontinuation 
Replaced the liver chemistry 
stopping criteria: Updated the 
section heading and added a 
statement to refer to Section 8.3.5 
for the details 
To comply with updated guidance 
from internal liver safety 
monitoring committee to enhance 
monitoring 
8.3.5. Hepatic Safety Monitoring, 
Evaluation, and Criteria for Study 
Intervention Interruption or 
Discontinuation 
Added tables for actions to be 
taken based on abnormal hepatic 
laboratory or clinical changes for 
participants with normal or near-
normal baseline and participants 
with elevated baseline 
8.3.5.1. Close Hepatic Monitoring 
8.3.5.2. Comprehensive Hepatic 
Evaluation 
8.3.5.3. Study Intervention 
Interruption or Discontinuation 
Updated the sections for actions to 
be taken based on abnormal 
hepatic laboratory or clinical 
changes for participants with 
normal or near-normal baseline 
and participants with elevated 
baseline 

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J3E-MC-EZDB(b) 
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Section # and Name
Description of Change
Brief Rationale 
9.5. Sample Size Determination 
Updated section with the revised 
randomization ratio  
To better assess the outcomes of 
the 50 mg and 100 mg study arms. 
10.6.1. Hepatic Evaluation Testing 
Updated hepatic evaluation testing 
table 
To clarify the hepatic monitoring 
guidance 
10.7. Appendix 7: Provisions for 
Changes in Study Conduct During 
Exceptional Circumstances 
Added a flow diagram illustrating 
screening and randomization 
For ease of interpretation 
10.9. Appendix 9: Protocol 
Amendment History (Newly 
added section) 
Inserted summary of amendment 
(a) rationale and changes 
To update the amendment history 
Throughout the protocol 
Minor formatting and editorial 
changes 
Minor, therefore, not detailed 
 

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J3E-MC-EZDB(b) 
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Table of Contents  
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................14 
1.3. 
Schedule of Activities (SoA) ..........................................................................................15 
2. 
Introduction ...................................................................................................................38 
2.1. 
Study Rationale ...............................................................................................................38 
2.2. 
Background .....................................................................................................................38 
2.3. 
Benefit/Risk Assessment ................................................................................................40 
2.3.1. 
Risk Assessment .............................................................................................................40 
2.3.2. 
Overall Benefit Risk Conclusion ....................................................................................41 
3. 
Objectives, Endpoints, and Estimands .......................................................................42 
4. 
Study Design ..................................................................................................................45 
4.1. 
Overall Design ................................................................................................................45 
4.2. 
Scientific Rationale for Study Design ............................................................................46 
4.3. 
Justification for Dose ......................................................................................................46 
4.4. 
End of Study Definition ..................................................................................................47 
5. 
Study Population ...........................................................................................................48 
5.1. 
Inclusion Criteria ............................................................................................................48 
5.2. 
Exclusion Criteria ...........................................................................................................50 
5.3. 
Lifestyle Considerations .................................................................................................52 
5.4. 
Screen Failures ................................................................................................................52 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................53 
6. 
Study Interventions and Concomitant Therapy ........................................................54 
6.1. 
Study Interventions Administered ..................................................................................54 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................55 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................55 
6.4. 
Study Intervention Compliance ......................................................................................56 
6.5. 
Dose Modification ..........................................................................................................57 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................57 
6.7. 
Treatment of Overdose ...................................................................................................57 
6.8. 
Concomitant Therapy .....................................................................................................58 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................59 
7.1. 
Discontinuation of Study Intervention ............................................................................59 
7.1.1. 
Hepatic Criteria for Study Intervention Interruption or 
Discontinuation ...............................................................................................................59 
7.1.2. 
QTc Stopping Criteria .....................................................................................................59 
7.1.3. 
Hypersensitivity Reactions .............................................................................................59 
7.1.4. 
Temporary Discontinuation ............................................................................................59 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................60 
7.3. 
Lost to Follow Up ...........................................................................................................61 

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J3E-MC-EZDB(b) 
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8. 
Study Assessments and Procedures.............................................................................62 
8.1. 
Efficacy Assessments .....................................................................................................62 
8.1.1. 
Primary Efficacy Assessment .........................................................................................62 
8.1.2. 
Other Efficacy Assessments ...........................................................................................62 
8.2. 
Safety Assessments .........................................................................................................66 
8.2.1. 
Physical Examinations ....................................................................................................66 
8.2.2. 
Vital Signs .......................................................................................................................66 
8.2.3. 
Electrocardiograms .........................................................................................................66 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................67 
8.2.5. 
Pregnancy Testing ...........................................................................................................67 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................68 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................69 
8.3.2. 
Pregnancy ........................................................................................................................70 
8.3.3. 
Injection-Site Reactions ..................................................................................................71 
8.3.4. 
Hypersensitivity Reactions .............................................................................................71 
8.3.5. 
Hepatic Safety Monitoring, Evaluation, and Criteria for Study 
Intervention Interruption or Discontinuation ..................................................................72 
8.3.6. 
Major Adverse Cardiovascular Events (MACE) ............................................................76 
8.3.7. 
Safety Topics of Special Interest ....................................................................................77 
8.4. 
Pharmacokinetics ............................................................................................................77 
8.4.1. 
Bioanalysis ......................................................................................................................78 
8.5. 
Pharmacodynamics .........................................................................................................78 
8.6. 
Genetics ..........................................................................................................................78 
8.7. 
Biomarkers ......................................................................................................................78 
8.8. 
Immunogenicity Assessments.........................................................................................79 
8.9. 
Medical Resource Utilization and Health Economics ....................................................79 
9. 
Statistical Considerations .............................................................................................80 
9.1. 
Statistical Hypotheses .....................................................................................................80 
9.1.1. 
Multiplicity Adjustment ..................................................................................................80 
9.2. 
Analyses Sets ..................................................................................................................80 
9.3. 
Statistical Analyses .........................................................................................................80 
9.3.1. 
General Considerations ...................................................................................................80 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................82 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................82 
9.3.4. 
Tertiary Endpoints Analysis ...........................................................................................82 
9.3.5. 
Safety Analyses ...............................................................................................................82 
9.3.6. 
Pharmacokinetic and Pharmacodynamic Analyses ........................................................83 
9.3.7. 
Immunogenicity Assessments .........................................................................................83 
9.3.8. 
Subgroup Analyses .........................................................................................................83 
9.4. 
Interim Analysis ..............................................................................................................84 
9.5. 
Sample Size Determination ............................................................................................84 
10. 
Supporting Documentation and Operational Considerations ..................................86 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................86 
10.1.1. Regulatory and Ethical Considerations ...........................................................................86 

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10.1.2. Financial Disclosure........................................................................................................86 
10.1.3. Informed Consent Process ..............................................................................................87 
10.1.4. Data Protection................................................................................................................87 
10.1.5. Committees Structure......................................................................................................88 
10.1.6. Dissemination of Clinical Study Data.............................................................................88 
10.1.7. Data Quality Assurance ..................................................................................................88 
10.1.8. Source Documents ..........................................................................................................90 
10.1.9. Study and Site Start and Closure ....................................................................................90 
10.1.10. Publication Policy ...........................................................................................................91 
10.1.11. Investigator Information .................................................................................................91 
10.1.12. Sample Retention ............................................................................................................91 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................92 
10.2.1. Laboratory Samples Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................96 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................97 
10.3.1. Definition of AE .............................................................................................................97 
10.3.2. Definition of SAE ...........................................................................................................98 
10.3.3. Definition of Product Complaints ...................................................................................99 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................99 
10.3.5. Reporting of SAEs ........................................................................................................101 
10.3.6. Regulatory Reporting Requirements .............................................................................101 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ........................................................103 
10.4.1. Definitions.....................................................................................................................103 
10.4.2. Contraception Guidance................................................................................................104 
10.5. 
Appendix 5: Genetics....................................................................................................105 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ..................................................................................................................106 
10.6.1. Hepatic Evaluation Testing ...........................................................................................106 
10.7. 
Appendix 8: Abbreviations and Definitions .................................................................112 
10.9. 
Appendix 9: Protocol Amendment History ..................................................................117 
11. 
References ....................................................................................................................121 
 

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J3E-MC-EZDB(b) 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of LY3540378 in Adults with Worsening 
Chronic Heart Failure with Preserved Ejection Fraction (HFpEF) 
Brief Title: Efficacy and Safety of LY3540378 in Adults with Worsening Chronic Heart 
Failure with Preserved Ejection Fraction 
Regulatory Agency Identifier Numbers: 
IND: 152593 
EudraCT Number: 2022-000780-48 
EU CT Number: 2023-505902-40-00 
Rationale: 
Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome 
complicated by a high prevalence of co-existing comorbidities with no known single 
pathophysiological process. Until the publication of the EMPEROR-Preserved trial 
(empagliflozin in HFpEF) in October 2021, no clinical trial had shown benefit of an 
experimental therapy in HFpEF. Empagliflozin has been approved for treatment for a wide 
range of patients with heart failure (HF), and sacubitril/valsartan was granted an expanded label 
for HF in adult patients with chronic HF particularly those with LVEF below normal. 
Study J3E-MC-EZDB (EZDB) will investigate the effects of 26-week treatment with 
LY3540378 on left atrial reservoir strain (LARS) in participants with worsening chronic 
HFpEF. This is the first Phase 2 study, and data from this study will inform dose decisions for 
the clinical development of LY3540378 for HFpEF. 
 
 

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Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
To demonstrate that LY3540378 
administered SC QW is superior to placebo 
for improving atrial myopathy in participants 
with worsening chronic HFpEF  
Change from baseline to Week 26 in LARS 
Secondary 
 
To compare the effect of LY3540378 
administered SC QW on participants with 
worsening chronic HFpEF 
Change from baseline to Weeks 12 and 26 in 
 Log-transformed NT-proBNP 
 LAEDVI 
 LAESVI 
 eGFR (CKD-EPI Creatinine-Cystatin equation 
[2021]) 
 serum creatinine, and 
 cystatin-C 
To assess safety and tolerability of 
LY3540378 administered SC QW  
 AE overall 
 safety topics of special interest 
Abbreviations: AE = adverse event; CKD-EPI = Chronic Kidney Disease-Epidemiology Collaboration; ECG = 
electrocardiogram; eGFR = estimated glomerular filtration rate; HFpEF = heart failure with preserved ejection 
fraction; LAEDVI = left atrial end-diastolic volume index; LAESVI = left atrial end-systolic volume index; 
LARS = left atrial reservoir strain; NT-proBNP = N-terminal pro-B-type natriuretic peptide; SC = 
subcutaneous; QW = weekly. 
Overall Design: 
Study EZDB is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study that 
will investigate the effects of treatment with LY3540378 compared with placebo on participants 
with worsening chronic HFpEF. 
Brief Summary: 
Study EZDB will investigate the hypothesis that LY3540378 administered subcutaneously (SC) 
weekly is superior to placebo for improvement of atrial myopathy in participants with 
worsening chronic HFpEF at Week 26.  
Participants with worsening chronic HFpEF will be treated with LY3540378 or placebo for 26 
weeks. Visits are scheduled every 
 weeks. 
The maximum total duration of study participation for each participant, including screening and 
safety follow-up periods, is approximately 
 weeks, across the following study periods: 
 Screening: 
 
 Double-Blind Treatment: 26 weeks, and 
 Safety Follow-Up: 
 

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J3E-MC-EZDB(b)
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Study Population:
In general, an individual may take part in the study if they
Have a known clinical
olic heart failure and are at least 18 
years of age or the legal age of consent in the jurisdiction in which the study is taking place 
at the time of signing the informed consent.
1 
bolus dose of IV diuretics or an out-of-hospital encounter (for example, Emergency Room, 
1 bolus dose of IV diuretics at that index 
event. A single continuous infusion is also allowed.
Males and females will be eligible for this study.
Are reliable and willing to make themselves available for the duration of the study and are 
willing to follow study procedures as required.
Abbreviations: HFpEF = heart failure with preserved ejection fraction; IV = intravenous; WHF = worsening heart 
failure.
In general, an individual may not take part in the study if they
Have any of the following cardiovascular conditions
o
o
acute coronary syndrome or percutaneous coronary intervention, coronary artery 
bypass graft, cardiac mechanical support implantation, within 3 months prior to 
V2 (randomization), or any other cardiac surgery planned during the study
o
LVAD or cardiac transplantation or have cardiac transplantation planned during 
the study
o
hypertrophic cardiomyopathy (obstructive or nonobstructive), restrictive 
cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac sarcoidosis, 
known amyloid cardiomyopathy, or inherited cardiomyopathy
o
uncorrected cyanotic cardiac disease affecting LV function
o
severe uncorrected valvular disease

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J3E-MC-EZDB(b) 
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 Are hospitalized for worsening HF event or received treatment for an urgent HF visit 
outside of being hospitalized with worsening heart failure (WHF), after V1 (screening) and 
before V2 (randomization) 
Number of Participants: 
Up to 456 participants will be randomly assigned to study intervention. 
Intervention Groups and Duration: 
Participants will be randomized 1:2:2:2 to the following intervention groups: 
 LY3540378 25 mg SC QW 
 LY3540378 50 mg SC QW 
 LY3540378 100 mg SC QW 
 Placebo 
Intervention administration is by subcutaneous injection, and dosing will occur every week. 
Ethical Considerations of Benefit/Risk: 
Considering the measures taken to minimize risk for the participants in this study, the potential 
risks identified in association with LY3540378 are justified by the anticipated benefits that may 
be afforded to participants with worsening chronic HFpEF. 
Data Monitoring Committee: No 
 

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J3E-MC-EZDB(b)
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1.2. 
Schema  

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J3E-MC-EZDB(b)
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1.3. 
Schedule of Activities (SoA)  
Screening 
Screening procedures may be conducted over more than 1 day, as long as all procedures are completed within the screening period. 
However, it is important to note that sample collections for the local and central laboratories and the ECG test should all be done on 
the same day. Other screening procedures, for example, ECHO may be conducted on another day. 
Telehealth visits 
Telehealth visits may be by telephone (or other technology), or on site if requested by the participant or required by local regulations. 
Unscheduled visits 
Unscheduled visits (UV) may occur as needed. The SoA reflects some of the procedures that may occur during these visits. 
Additional procedures may be performed per investigator discretion. 
 
 

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Visits 1 through 16 
 
SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria, 
review and 
confirm 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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J3E-MC-EZDB(b)
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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preexisting 
conditions and 
medical history, 
including relevant 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prespecified 
medical history 
(indication and 
history of interest) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior treatments 
for indication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Substance use 
(alcohol, caffeine, 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
tobacco use) 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Evaluation 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Weight 
X 
Vital signs 
X 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
Physical 
examination 
X 
12-lead ECG 
X 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
 
 
 
 
  
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
 
X 
 
Patient Global 
Impression of 
Status  Heart 
Failure Overall 
Health (PGIS-HF 
Overall Health) 
X 
 
Patient Global 
Impression of 
Change  Heart 
Failure Overall 
Health (PGIC-HF 
Overall Health) 
 
 
Patient Global 
Impression of 
Severity  Heart 
Failure Symptom 
Severity (PGIS-
HF Symptom 
Severity) 
X 
 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
Patient Global 
Impression of 
Change  Heart 
Failure Symptom 
Severity (PGIC-
HF Symptom 
Severity) 
 
Kansas City 
Cardiomyopathy 
Questionnaire 
(KCCQ) 
 
Laboratory Tests and Sample Collections 
 
Hematology 
X 
  
Clinical chemistry 
X 
  
Lipid panel 
 
  
Urinalysis 
 
  
Urine chemistry 
 
 

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J3E-MC-EZDB(b)
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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
Follicle-
stimulating 
hormone (FSH) 
X 
N-terminal pro-B-
type natriuretic 
peptide (NT-
proBNP) 
X 
Brain natriuretic 
peptide (BNP)  
X 

CONFIDENTIAL
J3E-MC-EZDB(b)
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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
 
 
 
 
  
Cystatin-C 
X 
  
Troponin, high 
sensitivity (hs-
cTnT) 
 
  
C-reactive 
protein, high 
sensitivity 
(hsCRP) 
 
  
Urinary albumin 
to creatinine ratio 
(UACR) 
 
  
Estimated 
glomerular 
filtration rate 
X 
 
 

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J3E-MC-EZDB(b)
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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
(eGFR)  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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J3E-MC-EZDB(b)
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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
 
 
 
 
 
Hemoglobin A1c 
(HbA1c) 
 
Human leukocyte 
antigen (HLA) 
 
Dehydroepiandros
terone (DHEA) 
 
Androstenedione 
 
Pharmacokinetic  
(PK) samples  
 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
   
Immunogenicity/
ADA samples  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetics sample 
 
Exploratory 
biomarker sample 
 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
Exploratory 
biomarker sample 
 
 
 
 
 
 
 
 
 
 
Register visit with 
IWRS 
X 
Randomization 
via IWRS 
 
Dispense study 
intervention via 
IWRS 
 
Administer study 
intervention on 
site 
 

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SP I  
Screening 
SP II  Treatment 
Comments 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Weeks from 
randomization 
2 
Visit interval 
tolerance (days) 
- 
Office 
(O)/telehealth (T) 
O 
 
Train participants 
and/or caregiver 
in study 
intervention 
administration 
 
  
Participant returns 
unused study 
intervention 
 
  

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Visits 17 through 24, ED, and Follow-Up 
Visit number 
17 
18 
19 
20 
21 
22 
23 
24 
ED 
UV 
801 
802 
  
Weeks from 
randomization 
Visit interval tolerance 
(days) 
Office (O)/Telehealth (T) 
Concomitant medications 
AEs 
Physical Evaluation 
  
Weight 
Vital signs 

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Visit number 
17 
18 
19 
20 
21 
22 
23 
24 
ED 
UV 
801 
802 
  
Weeks from 
randomization 
Visit interval tolerance 
(days) 
Office (O)/Telehealth (T) 
Physical examination 
12-lead ECG 
Echocardiogram 
  
  
  
  
  
  
  
X 
X 
  
  
  
  
 
 
  
  
  
  
Patient Global 
Impression of Status  
Heart Failure Overall 
Health (PGIS-HF Overall 
Health) 
  

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Visit number 
17 
18 
19 
20 
21 
22 
23 
24 
ED 
UV 
801 
802 
  
Weeks from 
randomization 
Visit interval tolerance 
(days) 
Office (O)/Telehealth (T) 
Patient Global 
Impression of Change  
Heart Failure Overall 
Health (PGIC-HF 
Overall Health) 
Patient Global 
Impression of Severity  
Heart Failure Symptom 
Severity (PGIS-HF 
Symptom Severity) 
Patient Global 
Impression of Change  
Heart Failure Symptom 
Severity (PGIC-HF 
Symptom Severity) 
Kansas City 
Cardiomyopathy 
Questionnaire (KCCQ)  
Laboratory Tests and Sample Collections 
  
Hematology 
  
  
Clinical chemistry 
  
  
Lipid panel 
  
  
Urinalysis 
  
  
Urine chemistry 
 
 

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Visit number 
17 
18 
19 
20 
21 
22 
23 
24 
ED 
UV 
801 
802 
  
Weeks from 
randomization 
Visit interval tolerance 
(days) 
Office (O)/Telehealth (T) 
N-terminal pro-B-type 
natriuretic peptide 
 
(NT-proBNP) 
 
Brain natriuretic peptide 
(BNP)  
  
Cystatin-C 
  
Troponin, high 
sensitivity 
 
(hs-cTnT) 
 
C-reactive protein, high 
sensitivity (hsCRP) 
  
Urinary albumin to 
creatinine ratio (UACR) 
  
Dehydroepiandrosterone 
(DHEA) 
 
Androstenedione 
 
Estimated glomerular 
filtration rate (eGFR) 
 
 
 
Pharmacokinetic (PK) 
samples  
 
 
Immunogenicity/ADA 
samples 
 
 

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Visit number 
17 
18 
19 
20 
21 
22 
23 
24 
ED 
UV 
801 
802 
  
Weeks from 
randomization 
Visit interval tolerance 
(days) 
Office (O)/Telehealth (T) 
 
 
 
 
 
 
  
Exploratory biomarker 
sample 
 
 
 
Exploratory biomarker 
sample 
 
 
 
 
 
 
 
 
 
  
Process visit using IWRS 
  
Dispense study 
intervention via IWRS 
  
Participant returns 
unused study 
intervention 
  
Administer study 
intervention weekly  
 

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Visit number 
17 
18 
19 
20 
21 
22 
23 
24 
ED 
UV 
801 
802 
  
Weeks from 
randomization 
Visit interval tolerance 
(days) 
Office (O)/Telehealth (T) 
 
 
 
 
Abbreviations: ADA = anti-drug antibody; AE = adverse events; BP = blood pressure; CVD = cardiovascular disease; ECG = electrocardiogram; ED = early 
discontinuation; eGFR = estimated glomerular filtration rate; HF = heart failure; ICF = informed consent form; IWRS = interactive web-response system; 
 NYHA = New York Heart Association; MI = myocardial infarction; O = office visit; PI = principal investigator; PK = 
pharmacokinetics; PR = pulse rate; SoA = schedule of activities; SP = study period; T = telehealth visit; V = visit.  
 
 
 

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Pharmacokinetic Sampling Schedule: 
 
Visit Number 
Week Relative to Randomization 
Collection Time Point Relative to Weekly Dose 
2 
Predosea, b and 2 to 4 hr post V2 dose 
3 
Predose 
5 
Predosea, b 
6 
24 to 96 hr post V5 dosea 
10 
Predose 
11 
24 to 96 hr post V10 dose 
14 
Anytime during visit 
16 
Predosea, b 
18 
Anytime during visita 
20 
Anytime during visit 
22 
Anytime during visit 
24 
Anytime during visita, b 
ED 
Anytime during visita, b 
UV 
Anytime during visit 
802 
Anytime during visitb 
Abbreviations: NA = not applicable; ED = early discontinuation; UV = unscheduled visit. 
a  On visits where triplicate ECGs are also measured, PK samples should be taken immediately (within 30 min) after ECG measurement. 
b
Immunogenicity (ADA) samples collected with PK at these visits. 

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2. 
Introduction  
LY3540378 is a recombinant fusion protein, which includes an 
 
 of a heavy chain only antibody fused via a flexible linker to the N-terminus of a single-
chain relaxin. Short-acting recombinant forms of relaxin have been shown to acutely improve 
dyspnea symptoms during HF events in clinical trials. Long-acting, LY3540378 is being 
developed for the treatment of patients with worsening chronic HFpEF. 
2.1. 
Study Rationale  
HFpEF is a heterogenous clinical syndrome complicated by a high prevalence of co-existing 
comorbidities with no known single pathophysiological process (van Heerebeek and Paulus 
2016). Until the publication of the EMPEROR-Preserved trial (empagliflozin in HFpEF) in 
October 2021 (Anker et al. 2021), no clinical trial had shown benefit of an experimental therapy 
in HFpEF. Empagliflozin has been approved for treatment for a wide range of patients with HF 
and sacubitril/valsartan was granted an expanded label for HF in adult patients with chronic HF, 
particularly those with LVEF below normal. 
Study J3E-MC-EZDB (EZDB) will investigate the effects of 26-week treatment with 
LY3540378 on LARS in participants with worsening chronic HFpEF. This is the first Phase 2 
study, and data from this study will inform dose decisions for the clinical development of 
LY3540378 for HFpEF. 
2.2. 
Background  
In the US, 6.2 million adults have HF (Benjamin et al. 2019), and the number of HF patients is 
expected to increase 46% by 2030 (Savarese and Lund 2017). Among all patients with HF, at 
least 50% present clinically with HFpEF (Owan et al. 2006) but its prevalence is increasing. It 
is estimated that by 2030, the prevalence of HF will increase an additional 46% and US HF 
costs are expected to be at least $70 billion per year with total cost of caring for HF patients to 
reach $160 billion (Heidenreich et al. 2013, 2022b). HFpEF patients, if anything, are expected 
to outnumber HF with reduced ejection fraction. 
The prevalence of HFpEF increases with age and is estimated to increase even more in those 
>70 years (Zile and Brutsaert 2002). Additionally, it is also more common in women. However, 
in the last 2 decades, the age incidence of HFpEF has declined but this may be regional. For 
example, in the ASIAN-HF registry, Asian patients with HFpEF were younger and more often 
men compared with predominantly Western patients (Tromp et al. 2018). Recent data in the 
USA also showed that African Americans (~65.6 years) presented with incident HFpEF at a 
younger average age than White patients (~76.7 years) (Lekavich et al. 2021). HFpEF is highly 
associated with comorbidities, more so than HF with reduced ejection fraction, including 
hypertension, obesity, diabetes mellitus, atrial fibrillation, CKD, and obstructive sleep apnea, 
and these comorbidities likely play a pathophysiological role in HFpEF (Solomon et al. 2007; 
Tromp et al. 2018, Gentile et al. 2021). 

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Management of HFpEF has largely been limited to symptom management and treatment of 
comorbidities, including blood pressure control, reduction in congestion, preservation of renal 
function, and control of arrhythmias (Yancy et al. 2013). However, in the most recent 2022-
updated ACC/AHA guidelines, SGLT-2i were designated a Class 2A indication as SGLT-2i are 
beneficial in decreasing HF hospitalizations and cardiovascular mortality in HFpEF patients 
(Heidenreich et al. 2022a). Conversely, sacubitril/valsartan, an angiotensin receptor-neprilysin 
inhibitor, was recently designated a Class 2B indication, based on the limited level of evidence, 
and may be considered for selected patients with LVEF on the lower end of this spectrum 
(Heidenreich et al. 2022a). 
The potential advantages of relaxin in HFpEF could be related to the short-term hemodynamic 
effects, such as mild blood pressure reduction and long-term benefits such as anti-inflammatory 
and anti-oxidative actions. The pleiotropic effects are related to the signaling cascade and its 
downstream mediators (Dschietzig et al. 2009).  
Human relaxin-2 (relaxin) is an endogenous hormone that plays a role in the hemodynamic and 
renovascular adaptive changes during pregnancy (Conrad 2011). Through the RXFP1 receptor, 
relaxin activates adenylate cyclase, protein kinase A, protein kinase C, phosphatidylinositol 3-
kinase, and extracellular signaling-regulated kinase and also interacts with nitric oxide signaling 
(Bathgate et al. 2013). Serelaxin, a recombinant human relaxin, was shown to acutely improve 
dyspnea symptoms and reduce worsening HF events through Day 5 in acute HF clinical trials 
after short-term IV infusion for 48 hours (Dschietzig et al. 2009; Conrad 2011). Since short-
term continuous infusion of short acting serelaxin demonstrated several beneficial 
hemodynamic changes in HF patients (Dschietzig et al. 2009; Ponikowski et al. 2014; Voors et 
al. 2014), chronic treatment with a long-acting relaxin may also potentially improve outcomes 
and reduce rehospitalizations and mortality in HF. 
LY3540378 is a recombinant fusion protein composed of an 
 
of a heavy chain only antibody fused via a flexible linker to the N-terminus of a single-chain 
relaxin. LY3540378 maintains similar selectivity between the receptors RXFP1 and RXFP2 as 
human relaxin-2. LY3540378 is anticipated to exhibit a human terminal half-life of 
 that supports once-weekly administration. In 3 preclinical models (in 
Sprague-Dawley rats and cynomolgus monkeys), LY3540378 has 
 
  
A detailed description of the chemistry, pharmacology, efficacy, and safety of LY3540378 is 
provided in the IB. 
Clinical Study EZDA preliminary results 
Study J3E-MC-EZDA (EZDA) is a 4-part, Phase 1, multicenter, participant and investigator 
blind, SAD, and MAD study in healthy participants to evaluate the safety, tolerability, and 
pharmacokinetics of 
 and once-weekly doses of LY3540378. Overall, LY3540378 was 
well tolerated. Related to treatment, only mild AEs were observed, with the most commonly 
reported AEs being administration site reactions, such as erythema, bruise, and injection-site 
reactions. 

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2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LY3540378 may be found in the IB. 
2.3.1. 
Risk Assessment  
Study intervention 
Study EZDA clinical data 
Preliminary results from Study EZDA in healthy participants indicate that LY3540378 is 
generally well tolerated (see Section 2.2) 
Nonclinical data 
Based on the nonclinical data, LY3540378 is not considered to be a high-risk compound. 
Potential risks 
Based on the current clinical data, nonclinical safety pharmacology and toxicology studies, 
potential risks for clinical study participants receiving LY3540378 are 
- 
hypotension-related events, and 
- 
systemic allergic or hypersensitivity reactions, or ISRs 
Based only on preclinical studies in rats, potential risks also include 
- 
reversible cervix hyperplasia, and 
- 
breast tumor. 
Mitigations for potential risks 
Hypersensitivity reactions will be managed per Section 8.3.4. 
Injection-site reaction assessments will occur throughout the study. 
As embryo or fetal studies have not been conducted prior to this study, women of childbearing 
potential will be excluded. 
Orthostatic hypotension will be monitored closely throughout the study, and blood pressure-
lowering drugs and diuretics dosing may be lowered as needed at the discretion of the study 
investigator. 
Participants with significant previous abnormal pap smear or mammography will be excluded 
from the study. 
Participants with history of cancer (within the last 3 years) or first-degree family history of 
breast cancer will be excluded from the study. 
Study procedures 
Echocardiogram (Echo) will be performed at 3 time points (see the SoA, Section 1.3). There are 
no specific risks as it is a non-invasive procedure to assess the overall function of the heart. 

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Benefit assessment 
The efficacy of LY3540378 for treating worsening chronic HFpEF has not been established. 
Participants may benefit by receiving personal health information from the physical 
examinations, frequent engagement with healthcare providers, and from other routine safety 
assessments performed in this study. 
2.3.2. 
Overall Benefit Risk Conclusion  
Considering the measures taken to minimize risk for the participants in this study, the potential 
risks identified in association with LY3540378 are justified by the anticipated benefits that may 
be afforded to participants with worsening chronic HFpEF. 

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3. 
Objectives, Endpoints, and Estimands  
Objectives 
Endpoints 
Primary 
 
To demonstrate that LY3540378 
administered SC QW is superior to placebo 
for improving atrial myopathy in participants 
with worsening chronic HFpEF  
Change from baseline to Week 26 in LARS 
Secondary 
 
To compare the effect of LY3540378 
administered SC QW on participants with 
worsening chronic HFpEF 
Change from baseline to Weeks 12 and 26 in 
 Log-transformed NT-proBNP 
 LAEDVI 
 LAESVI 
 eGFR (CKD-EPI Creatinine-Cystatin equation 
[2021]) 
 serum creatinine, and 
 cystatin-C 
To assess safety and tolerability of 
LY3540378 administered SC QW  
 AE overall 
 safety topics of special interest 
Tertiary 
 
To compare the effect of LY3540378 
administered SC QW on participants with 
worsening chronic HFpEF 
 Change from baseline to Weeks 12 and 26 in 
o LA emptying fraction 
o LVGLS 
o E/A 
o 
 
o LVM (LVMI) 
o high sensitivity troponin, (hs-cTnT) 
o NYHA class, and 
o BNP 
 Change from baseline to the average of Week 
 
and Week 26 in log-transformed NT-proBNP 
 Blood pressure and pulse rate 

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Clinical outcome events of HF 
Incidence of 
 All deaths (CV and non-CV) 
 HF event: 
o hospitalized (HF hospitalization) and 
o non-hospitalized HF events (urgent outpatient 
visits, unscheduled office, or emergency visit 
for HF)  
Change in outpatient hemodynamic CV 
medications 
Change in the dosing of 
 diuretics (loop and thiazide) 
 RAAS inhibitor 
 SGLT-2i 
 Beta blockers 
 ARNI, and 
 MRA 
To assess the effect of LY3540378 on 
patient-reported outcomes  
Change from baseline through Week 26 of 
 Severity of 
 
 
 
 
 
 
 PGIS-HF Overall Health 
 PGIC-HF Overall Health 
 PGIS-HF Symptom Severity 
 PGIC-HF Symptom Severity, and 
 KCCQ 
o Total Symptom Score 
o Clinical Summary Score, and 
o Overall Summary Score 
To assess presence of anti-LY3540378 
antibodies 
ADAs against LY3540378 including 
 treatment-emergent ADAs, and 
 neutralizing antibodies 
To assess LY3540378 PK and the 
relationship between LY3540378 dose or 
exposure and clinical endpoints and potential 
participant factors that may influence these 
relationships 
PK parameters of LY3540378 (Cmax, AUC). 
Dose or exposure-response analyses for key efficacy 
and safety endpoints 

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Abbreviations: ADA = anti-drug antibody; AE = adverse event; ARNI = angiotensin receptor neprilysin inhibitor; 
BNP = brain natriuretic peptide; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CV = 
cardiovascular; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HF = heart failure; 
HFpEF = heart failure with preserved ejection fraction; KCCQ = Kansas City Cardiomyopathy Questionnaire; 
LA = left atrium; LAEDVI = left atrial end-diastolic volume index; LAESVI = left atrial end-systolic volume 
index; LARS = left atrial reservoir strain; LVGLS = left ventricular global longitudinal strain; LVM = left 
ventricular mass; LVMI = left ventricular mass index; MRA = mineralocorticoid receptor antagonists; 
 
 NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart 
Association; PGIC-HF = Patient Global Impression of Change  Heart Failure; PGIS-HF = Patient Global 
Impression of Status  Heart Failure; PRO = patient-reported outcome; RAAS = Renin-angiotensin-aldosterone 
system; SC = subcutaneous; SGLT-2i = sodium-glucose cotransporter-2 inhibitor; QW = weekly. 
Primary estimand/coprimary estimand 
The primary clinical question of interest is 
What is the treatment difference in LARS change from baseline after 26 weeks of 
treatment in study participants who would have completed the treatment period? 
Efficacy estimand attributes 
This table describes the efficacy estimand attributes. 
Efficacy Estimand Attribute
Description
Population 
Participants who meet the inclusion criteria. 
Further details can be found in Sections 5 and 9.
Endpoint 
Change from baseline in LARS at Week 26.
Treatment condition 
The randomized treatment with allowance for dose modification 
based on hypotension (Section 6.5) and TD for safety (Section 
7.1.4).
Population-level summary 
Difference in mean absolute changes in LARS at Week 26 
between LY3540378 and placebo. 
Abbreviations: LARS = left atrial reservoir strain; TD = temporary discontinuation. 
Intercurrent events 
,
the 
hypothetical strategy. 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 LY3540378 under the ideal condition that all 
participants adhere to the randomized treatment. 
The same estimand for the primary objective will be used for the secondary clinical response 
endpoints. 
Unless specified otherwise, safety and tolerability assessments will be guided by an estimand 
comparing safety of LY3540378 doses with placebo irrespective of adherence to study 
intervention, including data collected during the treatment period and safety follow-up from all 
randomized participants who are exposed to at least 1 dose of study drug, regardless of 
adherence of study drug. 

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4. 
Study Design  
4.1. 
Overall Design  
Study EZDB is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study that 
will investigate the effects of treatment with LY3540378 compared with placebo on participants 
with worsening chronic HFpEF. 
Participants will be randomized 1:2:2:2 to the following intervention groups: 
 LY3540378 25 mg SC QW 
 LY3540378 50 mg SC QW 
 LY3540378 100 mg SC QW, and 
 placebo. 
Intervention administration is by subcutaneous injection, and dosing will occur every week. 
The maximum total duration of study participation for each participant, including screening and 
safety follow-up periods, is approximately 
 weeks, across the following study periods: 
 Screening: 
 
 Double-Blind Treatment: 26 weeks, and 
 Safety Follow-Up: 
 
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 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 visits 801 and 802 
Study personnel and participants complete all visit procedures described in the SoA. The 
from study intervention. 
An independent adjudication committee will adjudicate all-cause mortality and HF events. See 
Section 10.1.5 for details related to adjudicated events and committee structure. 

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4.2. 
Scientific Rationale for Study Design  
Primary endpoint rationale 
HFpEF patients have an atrial myopathy, and this can be measured non-invasively by LARS. 
LARS is associated with adverse clinical outcomes and poor prognosis in HFpEF. An increased 
PCWP with exercise and lower peak oxygen consumption on cardiopulmonary exercise testing 
is seen in worsening chronic HFpEF and associated with a reduced LARS (Patel et al. 2021). 
Thus, a stabilization and/or an increase in LARS with a therapy targeting LA myopathy is 
expected to improve outcomes in HFpEF. Additionally, LARS is also strongly related to LV 
strain, which is abnormal in HFpEF and LV strain is also associated with adverse outcome 
(Shah et al. 2015). Thus, LARS provides an integrated measures of LV and LA function and 
hemodynamics. 
Overall design description 
The 26 weeks  duration of the treatment period is a reasonable time frame to observe efficacy 
for the treatment of HFpEF, which will inform the dose level in future clinical studies. 
The follow-up visits after the last dose are designed to capture any additional safety signals. 
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 LY3540378 doses and placebo. 
In this study, collection of demographic information includes race and ethnicity. The scientific 
rationale is based on the need to assess variable response in safety and/or efficacy based on race 
or ethnicity. This question can be answered only if all the relevant data are collected. 
4.3. 
Justification for Dose  
LY3540378 Phase 2 doses of 25, 50, and 100 mg administered SC QW were selected in 
consideration of the following factors: 
 Safety and tolerability data from Phase 1 development in healthy participants. 
 Margin of safety for the highest dose of SC 100 mg QW in this study has anticipated 
exposure multiples between 3 and 25 to the no-observed-adverse-effect level in rats and 
monkeys in the 6-month toxicology studies.  
 Following QW dosing, LY3540378 SC 25 mg QW and 
 mg QW showed robust 
increase in effective renal plasma flow of at least 
 at Week  in healthy participants. 
 PK exposure-response analysis of all available SC effective renal plasma flow data 
following 
 and multiple doses of LY3540378 combined.  
 This dose range was chosen to improve the chances of achieving efficacy in HFpEF 
patients since limited information is available to guide translation of effective renal 
plasma flow pharmacology from healthy participants to clinical improvements in 
HFpEF patients. 
 The safety-efficacy data produced from the selected dose range will inform dose 
selection for future development of LY3540378 in the HFpEF patient population. 

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4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit shown in the SoA. 

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5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Have a known clinical 
must be at 
least 18 years of age or the legal age of consent in the jurisdiction in which the study is 
taking place at the time of signing the informed consent. 
Type of participant and disease characteristics 
2. Deleted 
3. Have experienced an index event, defined as  
A. 
1 bolus dose of IV diuretics, 
OR 
B. an out-of-hospital encounter (for example, Emergency Room, clinic visit, infusion 
1 bolus dose of IV diuretics at that index event. A single 
continuous infusion is also allowed. 
4. 
12 months prior to V1 (screening); as measured by 
echocardiography, radionuclide ventriculography, invasive angiography, MRI, or CT. 
 also include patient medical records, 
discharge n
referring physician 
 
5. Have NYHA Class II-IV symptomatology as assessed at V1 (screening). 
6. Had evidence of clinical HF syndrome consisting of 
A. Hospitalization for WHF with intravascular volume overload (the index event), as 
determined by the investigator, based on appropriate supportive documentation at 
randomization, 
 the following: 
 dyspnea 
 jugular venous distention 
 pitting edema in lower extremities (>1+) 
 ascites 
 pulmonary congestion on chest X-ray 
 pulmonary rales AND patient received treatment with IV diuretics. 
OR 
B. Treatment for an urgent visit outside of being hospitalized with WHF and 
intravascular volume overload (the index visit) requiring treatment with IV diuretics 

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1 IV bolus dose) such as in the outpatient setting/emergency 
room/observation unit/infusion clinic with a clinical response within the past 2 weeks 
prior to randomization. Urgent visit is defined as an unplanned visit for HF defined by 
 the following: 
 dyspnea 
 jugular venous distention 
 pitting edema in lower extremities (>1+) 
 ascites 
 pulmonary rales on lung examination. 
7. NT-proBNP (>300 [sinus rhythm] or 600 pg/mL [atrial fibrillation or atrial flutter] OR 
BNP (>100 [sinus rhythm] or 200 pg/mL [atrial fibrillation or atrial flutter]) at screening 
(Visit 1, determined by local laboratory) 
Note: The presence or absence of atrial fibrillation or atrial flutter to determine the 
appropriate cut-off for a given BNP or NT-proBNP sample should be evaluated using 
the ECG performed at V1 (screening) prior to the collection of the BNP or NT-proBNP 
sample. 
8. eGFR of >20 mL/min/1.73 m2 at V1 (screening; determined by local laboratory), 
derived from serum creatinine values, age, and sex based on the CKD-EPI equation 
(Inker et al. 2021).  
9. If the participant is screened (V1): 
A. after the index event in the outpatient setting, the diuretic doses must have transitioned to 
oral loop diuretic before randomization (V2). In other words, chronic oral diuretic should 
have been prescribed and/or administered, OR 
B. during the index event (such as while hospitalized or at an urgent clinic visit or 
emergency room), the diuretic can be administered either as an IV or oral formulation 
prior to randomization (V2). 
Sex and contraceptive/barrier requirements 
10.  Males and females will be eligible for this study. 
a. Women not of childbearing potential may participate in this trial. (WOCBP are 
excluded from the trial.)  
See Appendix 10.4 for definitions. 
b. Males who agree to use highly effective or effective methods of contraception 
may participate in this trial.  
See Appendix 10.4 for definitions. 
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Appendix 10.4. 
Informed consent 

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11. 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 
12. Are reliable and willing to make themselves available for the duration of the study and 
are willing to follow study procedures, such as 
 self-inject intervention, and 
 store and take provided study interventions as directed. 
Note: Persons with physical limitations or unable to perform the injections must have 
the assistance of an individual trained to inject the intervention or come onsite for 
weekly injection. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Cardiovascular conditions 
13. Prior documentation 
 
14. Have had acute coronary syndrome or percutaneous coronary intervention, coronary 
artery bypass graft, cardiac mechanical support implantation, and PVA (pulmonary vein 
isolation ablation) within 3 months prior to V2 (randomization), or any other cardiac 
surgery planned during the study. 
15. Have had LVAD or cardiac transplantation or have cardiac transplantation planned 
during the study. 
16. Have hypertrophic cardiomyopathy (obstructive or nonobstructive), restrictive 
cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac sarcoidosis, 
known amyloid cardiomyopathy, or inherited cardiomyopathy. 
17. Deleted 
18. Have a history of an uncorrected cyanotic cardiac disease affecting LV function. 
19. Have a severe uncorrected valvular disease. 
20. The index admission or index visit for worsening chronic HF was not triggered 
primarily by intravascular volume overload but triggered by 
 pulmonary embolism 
 cerebrovascular accident  
 acute myocardial infarction (Type 1 MI) 
 significant arrhythmia, for example, sustained ventricular tachycardia, or 
bradycardia with sustained ventricular arrhythmia <45 bpm (however, any atrial 
fibrillation or flutter is permitted) 
 serious or systemic infection 
 severe anemia, or 
 exacerbation of COPD. 
21. In the opinion of the PI, have any medical complication arising during HF index 
admission that prolongs the hospitalization.   

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22. Time from hospitalization discharge to randomization is >2 weeks for participants who 
are not randomized during hospitalization OR duration of the HF hospitalization lasting 
more than 4 weeks. 
23. Are hospitalized for worsening HF event or received treatment for an urgent HF visit 
outside of being hospitalized with WHF, after V1 (screening) and before V2 
(randomization) (see Section 5.4 for rescreening). 
Other medical conditions 
24. Have a chronic pulmonary/lung condition (COPD, pulmonary arterial hypertension, 
etc.) as defined by chronic oxygen dependence. Night-time oxygen is not exclusionary. 
25. Uncorrected thyroid disease. 
26. During the index event, hemoglobin <10 g/dL (or local lab at screening). However, the 
participant is considered eligible if subsequently the hemoglobin 
 g/dL before V2 
(randomization).  
27. Patients requiring dialysis at screening. 
28. Have, within 3 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. 
29. Male and female participants with a personal or family history (first-degree relatives) of 
breast cancer. 
30. Women with a history of a mammography with clinically significant abnormal findings. 
31. Women with a history of clinically significant abnormal pap smear. 
32. Patients have any history of bleeding or coagulation disorder causing a bleeding 
diathesis, other bleeding diathesis, or significant, nontraumatic bleeding episodes, such 
as from a gastrointestinal source. 
33. Symptomatic hypotension or a systolic BP <100 mmHg at the Screening Visit and on 
the day of V2 (randomization). 
34. 
 (randomization). 
35. Have a history of or current significant psychiatric disorders considered clinically 
significant in the opinion of the investigator. 
36. Chronic alcohol or drug abuse or any condition that, in the inve
them an unreliable trial participant or unlikely to complete the trial. 
37. Any other clinical condition that would jeopardize the 
 safety while 
participating in this trial or may prevent the participant from adhering to the trial 
protocol. 
Diagnostic assessments 
38. During the index event, evidence of hepatic insufficiency classified as: 
 a documented Child-PUGH B or C, 
 a documented ALT or AST >5x ULN, or 
 evidence of active/chronic liver disease at the PI discretion. 

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39. Have a suboptimal ECHO image quality assessed by a central imaging laboratory at 
screening. 
Prior/concomitant therapy 
40. Have received IV inotropic therapy within 30 days before the Screening Visit. 
 
 
41. Are currently treated with hormone replacement therapy at the time of screening, 
including but not limited to testosterone, estrogen, and DHEA. 
Prior or concurrent clinical study experience 
42. Are currently enrolled in any other clinical study involving an intervention or any other 
type of medical research, judged not to be scientifically or medically compatible with 
this study by the investigator. 
43. Have participated, within the last 30 days, in a clinical trial involving an intervention. If 
the previous intervention has a long half-life, 3 months or 5 half-lives, whichever is 
longer, should have passed. 
Other exclusions 
44. Are unwilling to have a cardiac echocardiogram. 
45. Are Lilly employees or are employees of any third party involved in the study who 
require exclusion of their employees. 
46. 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. 
47. Are unsuitable for inclusion in the study in the opinion of the investigator. 
48. Index event is the first (de novo) occurrence or diagnosis of HFpEF. 
5.3. 
Lifestyle Considerations  
Participants must not donate blood or sperm for the duration of the study and for 135 days 
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 enrolled in the study. 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 publishing requirements and to 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 
another, subsequent worsening HF index 
event, provided that there are at least 30 days between subsequent worsening HF index events. 

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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 (within 24 hours of the 
initial, local laboratory test) without the participant having to be rescreened. 
Note that participants who are rescreened will need to have a repeat echocardiogram collected 
after the subsequent worsening HF index event. 
Rescreened participants should be assigned a new participant number for every screening or 
rescreening event. 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable. 

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6. 
Study Interventions and Concomitant Therapy  
Study intervention is defined as any medicinal product(s)  or medical device(s) intended to be 
administered to or used by a study participant according to the study protocol. 
6.1. 
Study Interventions Administered  
Intervention Name 
LY3540378 
Placebo 
Dosage Level(s) 
25 mg 
50 mg 
100 mg 
N/A 
Route of 
Administration 
Subcutaneous injection 
Authorized as defined 
by EU CTR No 
536/2014a 
Not authorized as defined by EU CTR 
Abbreviations: EU CTR = European Union clinical trial regulation. 
a 
Authorized investigational medicinal product  means a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with Directive 2001/83/EC, 
irrespective of changes to the labeling of the medicinal product, which is used as an investigational medicinal 
product; Authorized auxiliary medicinal product  means a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, 
irrespective of changes to the labeling of the medicinal product, which is used as an auxiliary medicinal 
product. 
Packaging and labeling 
Study interventions will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
LY3540378 frequency of administration and guidance for missed doses 
LY3540378 should be administered once weekly at approximately the same time and day each 
week. All injections will need to be completed within 10 minutes. The actual date, time, and 
injection-site location of all dose administrations will be recorded in the diary by the 
participant. If a dose is missed, it should be administered as soon as possible if at least 3 days 
(72 hours) remain until the next scheduled dose. If less than 3 days remain before the next 
scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled 
day. In each case, participants can then resume their regular once-weekly dosing schedule. 
The 
 administration can be changed, if necessary, only if the last dose has been 
administered at least 3 days earlier. 
Anatomical location of injections 
Subcutaneous injections of LY3540378 and placebo will be administered rotating between left 
and right abdominal regions, and upper and lower quadrants. Injections may be administered in 
the thigh, arm, or buttock, at the discretion of PI. Refer to the Instructions for Use for complete 
instructions on dose administration. 

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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. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. The participant or caregiver 
may also administer the study intervention. All study interventions 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. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
Participant responsibilities 
In-use storage conditions are expected to be followed according to the Instructions for Use 
provided by the sponsor. Study participants will be trained on the proper storage and handling 
of the study intervention. 
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. 
For participants who joined study before amendment (b), they were randomized 1:1:1:1 to the 
following intervention groups: 
 LY3540378 25 mg SC QW 
 LY3540378 50 mg SC QW 
 LY3540378 100 mg SC QW, and 
 placebo. 
For participants who joined study after amendment (b), will be randomized 1:2:2:2 to the above 
intervention groups.  
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. 
Study intervention will be dispensed at the study visits summarized in SoA. 
Returned study intervention should not be re-dispensed to the participants. 

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Stratification 
For between-group comparability, participant randomization will be stratified by 
 evidence of atrial fibrillation or atrial flutter on the screening ECG (Yes, No) 
 region (North America, Latin America, Europe and other countries, Asia). 
Randomization into 1 stratum may be discontinued at the discretion of the sponsor. 
To avoid over-representation of participants with atrial fibrillation in the trial, randomization of 
participants with atrial fibrillation on their screening ECG may be stopped at the discretion of 
the sponsor when this randomized cohort comprises approximately 40% of the total planned 
randomized population. The exact proportion of participants randomized with atrial fibrillation 
and/or atrial flutter will be determined by the sponsor following a review of the blinded 
screening characteristics of this group compared to those without atrial fibrillation and/or atrial 
flutter. 
Blinding 
This is a double-blind study in which participants, care providers, investigators, outcomes 
assessors, etc. are blinded to study intervention. The IWRS will be programmed with blind-
breaking instructions. In case of an emergency, the investigator has the sole responsibility for 
articipant 
safety must always be the first consideration in making such a determination. If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
tion assignment unless this could delay 
the sponsor must be notified immediately within 24 hours of this occurrence. The date and 
reason that the blind was broken must be recorded. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to 
have the participant remain in the study, the investigator must obtain specific approval from a 
sponsor 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 dose of 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 will be provided to the sponsor as requested. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at visits indicated in the SoA (Section 1.3). Compliance will be 
assessed by counting returned vials and documented in the source documents. 
A record of the number of LY3540378 vials dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions, will also be 
recorded in the CRF. 

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6.5. 
Dose Modification  
This section applies to participants receiving 100 mg (or matching placebo) only. 
Holding and potential dose modification procedures apply if the participant experiences the 
following TD criteria: 
 symptomatic hypotension or  
 SBP <90 mmHg 
When any of the above TD criteria are met, hold study intervention, and document in the CRF. 
The participant continues attending visits and performing all other procedures and assessments 
as described in the SoA (Section 1.3). 
At each visit, the investigator will review TD criteria. Participants who continue to meet TD 
criteria will continue to have their dose held. 
TD criteria met for 
Then 
If participant no longer meets 
TD criteria on next visit, then 
restart dose at 
First occurrence  
Investigator adjusts concomitant 
medications AND holds study drug. 
100 mg 
Second occurrencea  
Investigator holds study drug. 
100 mg 
Third occurrencea 
Investigator holds study drug and 
contacts the sponsor.  
50 or 100 mg. And up titrate 
from 50 to 100 mg or lower 
back from 100 to 50 mg as 
needed, per investigator 
judgment  
Abbreviation: TD = temporary discontinuation. 
a 
Occurrence is defined as each visit the participant presents meeting TD criteria, whether as consecutive 
visits or intermittent visits, and is cumulative through the study. 
Note: Participants in the 100-mg group who are receiving placebo continue to receive placebo when dosing is 
resumed. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
LY3540378 will not be made available to participants after conclusion of the study. 
6.7. 
Treatment of Overdose  
For this study, any dose of study intervention greater than the dose assigned through 
randomization will be considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. 

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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 or whether the dose should be reduced 
 consider holding diuretics and/or blood pressure-lowering medications if clinically 
appropriate 
 closely monitor the participant for any AE or SAE and laboratory abnormalities, and 
 obtain a plasma sample for PK analysis within 3 days from the date of the last dose of 
study intervention if requested by the medical monitor (determined on a case-by-case 
basis). 
6.8. 
Concomitant Therapy  
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with 
 reason for use 
 dates of administration including start and end dates, and 
 dosage information including dose and frequency for concomitant therapy of special 
interest. 
Standard of care for heart failure 
Both American College of Cardiology/American Heart Association and European Society of 
Cardiology guidelines recommend symptom management with diuretic agents in patients with 
excess volume, as well as aggressive risk factor management for comorbidities for the treatment 
of HFpEF (van der Meer et al. 2019). Optimization of volume status and proactive adjustment 
of diuretic doses will help control symptoms and volume overload. SGLT-2i is now a Class 2A 
indication in participants with HFpEF, as SGLT-2is have been shown to decrease HF 
hospitalizations and cardiovascular mortality (Heidenreich et al. 2022a). 
Participants should remain on stable doses of medications to treat comorbidities such as 
hypertension. Dose reduction or discontinuation of such background therapies should be 
av
discretion of the investigator. 
The sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for remaining study visits. 
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study, or 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons. 
7.1.1. 
Hepatic Criteria for Study Intervention Interruption or Discontinuation  
See Section 8.3.5 for hepatic criteria for study intervention interruption or discontinuation. 
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 
) 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. 
7.1.3. 
Hypersensitivity Reactions  
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
investigator is uncertain about whether a systemic hypersensitivity reaction has occurred and 
whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor. 
7.1.4. 
Temporary Discontinuation  
In certain situations, after randomization, the investigator may need to temporarily discontinue 
(interrupt) study intervention, for example, due to an AE, ISR, or a clinically significant 
laboratory value. If study intervention interruption is due to an AE, the event is to be 
documented and followed according to the procedures in Section 8.3 of this protocol. Every 
effort should be made by the investigator to maintain patients on study intervention and to 
restart study intervention after any temporary interruption, as soon as it is safe to do so. The 
data related to temporary interruption of study intervention will be documented in source 
documents and entered in the eCRF. 
Criteria for temporary discontinuation 

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The investigator may temporarily interrupt study treatment, due to an AE, clinically significant 
laboratory value, hospital visits, travel, or shortage of study treatment supply. 
Investigator should inform the sponsor when study intervention has been temporarily 
discontinued after 
 for symptomatic hypotension. This information should 
be documented by the investigator.
For participants receiving 100 mg, certain TD criteria (symptomatic hypotension or SBP <90 
mmHg) could result in dose modification. See Section 6.5. 
Guidance when temporary discontinuation of study intervention occurs 
Every effort should be made by the investigator to maintain participants in the study and to 
restart study intervention promptly, as soon as it is safe to do so. 
Participants will continue their study visits and follow-up according to the SoA. 
Participants should resume the dose prescribed before the temporary dosing interruption at the 
discretion of the investigator. 
Recording temporary discontinuation of study intervention 
The dates of study intervention interruption and restart must be documented in source 
documents and entered on the CRF. 
Participant noncompliance should not be recorded as interruption of study intervention on the 
CRF. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
 at any time at 
 own request 
 at the request of 
 designee, for example, parents or legal guardian 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 if enrolled in any other clinical study involving an investigational product, or enrolled in 
any other type of medical research judged not to be scientifically or medically 
compatible with this study. 
At the time of discontinuing from the study, if possible, the participant will complete 
procedures for an early discontinuation visit and safety follow-up, as shown in the SoA. If the 
participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 

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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  
The primary efficacy measurement in this study is the change in LARS from baseline to Week 
26. LARS is a non-invasive assessment of elevated left filling pressures and correlates with 
PCWP. LA reservoir strain quantifies the deformation of the left atrium during atrial filling, 
whereby less deformation (lower strain) has been associated with adverse LA remodeling and 
increased fibrosis. 
The LA plays an integral role in the pathophysiology and prognosis of HFpEF. Beyond LA 
size, LA mechanical dysfunction has gained a considerable amount of attention recently. LARS 
measured by two-dimensional (2D) speckle-tracking echocardiography, is a key LA parameter 
quantifying LA compliance and function. LARS is also a sensitive parameter to assess LV 
filling pressure (Tan et al. 2021) and correlates with PCWP (Wakami et al. 2009). Morris et al. 
(2018) shows incremental diagnostic value of LARS over LA volume in detecting LV diastolic 
dysfunction. Lower LARS is associated with higher risk of HF hospitalization and CV death 
(Santos et al. 2016), after adjusting for LA volume. 
8.1.2. 
Other Efficacy Assessments  
Secondary efficacy assessments for this study are 
 Log-transformed NT-proBNP change from baseline to Week 12 and 26 (see Section 
8.1.2.1) 
 LAEDVI change from baseline to Week 12 and 26 (see Section 8.1.2.2) 
 LAESVI change from baseline to Week 12 and 26 (see Section 8.1.2.2) 
 eGFR, calculated by CKD-EPI Creatinine-Cystatin equation (2021), change from 
baseline to Week 12 and 26 (see Section 8.1.2.1) 
 serum creatinine change from baseline to Week 12 and 26 (see Section 8.1.2.1), and 
 Cystatin-C change from baseline to Week 12 and 26 (see Section 8.1.2.1). 

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8.1.2.1. 
Pharmacodynamic Markers  
At times specified in the SoA, blood samples will be collected to measure changes in levels of 
these markers to assess worsening chronic HFpEF: 
 NT-proBNP 
 Creatinine, to calculate eGFR 
 Cystatin-C, to calculate eGFR, and 
 BNP 
8.1.2.2. 
Echocardiogram  
Two-dimensional ECHO with pulsed and tissue Doppler sampling will be performed locally by 
personnel qualified by experience and training as specified in the SoA (Section 1.3). 
Each ECHO will be transmitted electronically to a designated central imaging laboratory for 
interpretation and analysis. The ECHO done at screening must be confirmed by the central 
ECHO laboratory prior to enrollment. If an ECHO demonstrates imaging quality issues, a 
limited repeat ECHO will be repeated at the discretion of the central ECHO laboratory. 
The table below presents the ECHO measurements at each time point. 
 
Study EZDB Echocardiogram Parameters 
Echocardiogram Parameter
2D echo
LV volumes
o LVEDVI 
o LVESVI 
 LVEF 
 LA volumes 
o LAEDVI 
o LAESVI 
 LA emptying fraction 
LVM (LVMI)
Doppler 
E/A
 RVSP 
TR 
Tissue Doppler 
E/e
Color Doppler (Qualitative Measurements 
only) 
Mitral regurgitant severity
 Aortic regurgitant severity 
Tricuspid regurgitant severity 
Speckle tracking 
LARS
Abbreviations: LA = left atrium; LAEDVI = left atrial end-diastolic volume index; LAESVI = left atrial end-
systolic volume index; LARS = left atrial reservoir strain; LV = left ventricle; LVGLS = left ventricular global 
longitudinal strain; LVEDVI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection 
fraction; LVESVI = Left ventricular end-systolic volume index; LVM = left ventricular mass; LVMI = left 
ventricular mass index; RVSP = right ventricular systolic pressure; TR = tricuspid regurgitation.  

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8.1.2.3. 
Patient-Reported Outcomes  
The self-administered questionnaires will be translated into the native language of the region 
and administered at the site during the designated visits in the SoA. 
The questionnaires should be completed before the participant has discussed their medical 
condition or progress in the study with the investigator or study personnel. Preferred 
administration order of these questionnaires is: 
1. 
  
2. 
3. 
 
4. 
 
5. PGIS-HF Overall Health 
6. PGIC-HF Overall Health 
7. PGIS-HF Symptom Severity 
8. PGIC-HF Symptom Severity, and 
9. KCCQ 
8.1.2.3.1. 
  
 
8.1.2.3.2. 
  
 
8.1.2.3.3. 
  
 
 
8.1.2.3.4. 
  
 
 
8.1.2.3.5. Patient Global Impression Scales  
In addition to the instruments above, study participants will complete 2 PGIS-HF and 2 PGIC-
HF scales to obtain a global assessment of patient s overall health status and HF symptom 
severity.
 

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PGIS- HF Overall Health 
The PGIS-HF Overall Health was specifically developed for this study. 
 
PGIS- HF Symptom Severity 
The PGIS-HF Symptom Severity was specifically developed for this study. 
 
 
PGIC- HF Overall Health 
The PGIC-HF Overall Health was specifically developed for this study.
 
PGIC- HF Symptom Severity 
The PGIC-HF Symptom Severity was specifically developed for this study.
8.1.2.3.6. Kansas City Cardiomyopathy Questionnaire  
The KCCQ is a 23-item, participant self-administered questionnaire that assesses impacts of HF 
 
 Physical Limitation (6 items) 
 Symptom Stability (1 item) 
 Symptom Frequency (4 items) 
 Symptom Burden (3 items) 
 Self-Efficacy (2 items) 
 Quality of Life (3 items), and 
 Social Limitation (4 items). 
Each of the 23 individual items are answered on Likert scales of varying lengths (5-point, 6-
point, or 7-point scales). Domain scores are obtained by averaging the associated individual 
items and transforming the score to a 0 to 100 range. Higher scores indicate better health status. 
Summary scores are obtained by combining select domain scores: 
 Total Symptom Score: mean of the Symptom Frequency and Symptom Burden scores 
 Clinical Summary Score: mean of the Physical Limitation and Total Symptom scores, 
and 
 Overall Summary Score: mean of the Physical Limitation, Total Symptom, Quality of 
Life, and Social Limitation scores. 
The Total Symptom Score, Clinical Summary Score, and Overall Summary Score will be used 
for the tertiary endpoints. 

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8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations  
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight will 
also be measured and recorded, as specified in SoA. 
Additional assessments should include clinical signs and symptoms related to HF, and ISRs. 
8.2.2. 
Vital Signs  
BP (supine and standing), pulse rate, respiratory rate, and temperature 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 supine at least 5 minutes, before 
obtaining an ECG tracing, collection of blood samples for laboratory testing, and prior to study 
drug administration when feasible. For orthostatic measurements, participants should be supine 
for at least 5 minutes and stand for at least 3 minutes. Unscheduled orthostatic vital signs 
should be assessed, if possible, during any AE of dizziness or posture-induced symptoms. BP 
may be remeasured within 30 minutes at investigator discretion. 
8.2.3. 
Electrocardiograms  
For each participant, a 12-lead digital ECG will be collected as replicates as indicated in the 
SoA. ECGs must be recorded before collecting any blood samples. Participants must be supine 
for approximately 5 to 10 minutes before ECG collection and remain supine but awake during 
ECG collection. Consecutive replicate ECGs will be obtained at approximately 1-minute 
intervals. ECGs may be obtained at additional times, when deemed clinically necessary. 
At time points that require triplicate ECG, 3 individual ECG tracings should be obtained as 
closely as possible in succession, but no more than 2 minutes apart.  
If triplicate 12-lead ECGs and PK sampling are scheduled for the same visit, PK sample should 
be collected within 30 minutes after triplicate ECG. 
ECGs will be interpreted by a qualified physician (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 at the relevant visit(s) and for 
immediate participant management, should any clinically relevant findings be identified. 
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the participant for symptoms (for example, palpitations, 
near syncope, syncope) to determine whether the participant can continue in the study. 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 from at least 1 of the replicate ECGs from each time point. 

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Digital ECGs will be electronically transmitted to a Lilly-designated central ECG 
laboratory. The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database. At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements. 
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the 
final study report, in which case the overread data would be used. 
8.2.4. 
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. 
 
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 and standard collection requirements. 
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. 
8.2.5. 
Pregnancy Testing  
Pregnancy testing will not be performed as only women not of childbearing potential may 
participate in this study. 

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8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3: 
 AEs 
 SAEs 
 PCs 
These events will be reported by the participant or, when appropriate, by a caregiver, surrogate, 
or the participant s legally authorized representative. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or study (see Section 7). 
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 or contacts. All SAEs and safety topic of special interest as defined in Section 
8.3.7 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. 

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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 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 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hr 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 hr of 
awareness 
SAE CRF  
SAE 
paper 
form 
SAEa  after 
study 
participation 
has ended and 
the investigator 
becomes aware 
After 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of 
study 
intervention 
135 days 
after the last 
dose  
Within 24 hr (see 
Section 8.3.2) 
Pregnancy CRF 
Pregnancy 
paper 
form 

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Event 
Collection 
Start 
Collection 
Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method 
of 
Reporting 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of 
study 
intervention 
End of 
study 
intervention 
Within 24 hr of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of 
study 
intervention 
End of 
study 
intervention 
Within 1 business 
day of awareness 
PC form 
N/A 
Updated PC 
information 
 
 
As soon as possible 
upon site awareness 
Originally 
completed PC 
form with all 
changes signed 
and dated by the 
investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
PC = product complaint; SAE = serious adverse event. 
a SAEs should not be reported unless the investigator deems them to be possibly related to 
study treatment or study participation. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive study intervention. 
After learning of a pregnancy in the female partner of a study participant, the investigator  
 will 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 

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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. 
weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any poststudy pregnancy related SAE considered reasonably related to the study intervention 
by the investigator will be reported to the sponsor as described in protocol Section 8.3.1. While 
the investigator is not obligated to actively seek this information in former study participants, 
they may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. If the participant is discontinued from the study, follow the standard 
discontinuation process and continue directly to the follow-up phase. The follow up on the 
pregnancy outcome should continue independent of intervention or study discontinuation. 
8.3.3. 
Injection-Site Reactions  
Symptoms of a local ISR will be assessed through spontaneous ISR reporting. 
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 reporting, collect an immunogenicity and PK sample. 
8.3.4. 
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 AE 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. 

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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. 
8.3.5. 
Hepatic Safety Monitoring, Evaluation, and Criteria for Study Intervention 
Interruption or Discontinuation  
The following tables summarize actions to take based on abnormal hepatic laboratory or clinical 
changes. 
 
Initiate or 
continue 
 close hepatic 
monitoring 
Initiate  
comprehensive 
evaluation 
Interrupt or 
discontinue  
study 
intervention
X 
N 
X 
a 
X 
X 
X
 
X 
X
b
X 
X
X 
X 
X
X 
X 
X
X 
a 
 
X 
X
X 
 
X 
X
X 
a 
X 
X
X 
b 
X 
X 
X 
Abbreviations: ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; INR = 
international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal.  
a 
threshold for TBL may be higher. 
b Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
 

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Participants with elevated baseline (ALT, AST, or ALP 
 
If this 
 
Initiate or 
continue 
close hepatic 
monitoring 
Initiate  
comprehensive
evaluation
Interrupt 
or 
discontinue 
study 
intervention
 
X 
 
X 
a 
X 
 
(whichever occurs first)
X 
X 
 
 
X 
X 
 
(whichever occurs first) with hepatic signs or symptomsb
X 
X 
X 
 
(whichever occurs first) for more than 2 weeks 
X 
X 
X 
first)
X 
X 
X 
 
a
X 
X 
X 
 
X 
X 
X 
ALP 
a 
X 
X 
X 
b 
X 
X 
X 
Abbreviations: ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; TBL = 
total bilirubin; ULN = upper limit of normal. 
a  
 
b Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
8.3.5.1. 
Close Hepatic Monitoring  
 
Participants with normal or near-normal baseline 
liver enzymes (ALT, AST, or ALP <1.5x ULN)
Participants with elevated baseline liver enzymes 
(ALT, AST or ALP
or
or
or
or
a
 a
Abbreviations: ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; TBL = 
total bilirubin; ULN = upper limit of normal. 
a 
. 

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 Laboratory tests (Section 10.6), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, creatine kinase, and complete blood count with differential, 
should be checked within 48 to 72 hours of the detection of elevated liver tests to confirm 
the abnormality and to determine if it is increasing or decreasing. 
 If the abnormality persists, clinical and laboratory monitoring should continue at a 
frequency of 
 until levels normalize or return to approximate baseline 
values.  
 In addition to laboratory tests, basic 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 
o current symptoms 
o recent illnesses, for example, systemic infection, hypotension, or seizures 
o recent travel 
o concomitant medications, including over-the-counter  
o herbal and dietary supplements 
o history of alcohol drinking, and  
o other substance abuse. 
8.3.5.2. 
Comprehensive Hepatic Evaluation  
 
Participants with normal or near-normal baseline 
liver enzymes (ALT, AST, or ALP <1.5x ULN) 
Participants with elevated baseline liver enzymes (ALT, AST, 
or ALP
 
or 
 
(whichever occurs first) or 
or
or 
 with hepatic signs or 
symptomsa or
 
(whichever occurs first) with hepatic signs or symptomsa or 
or 
 
(whichever occurs first) for more than 2 weeks or
or
or
b or INR 
 
 
(whichever occurs first) and 
 b
Abbreviations: ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; INR = 
international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal. 
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
b 
 

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Comprehensive hepatic evaluation should include these actions: 
 
 
o physical examination and a thorough medical history, as outlined in Sections 1.3 
and 8.2.1, and 
o 
 
 
international normalized ratio 
 
 
 
 
 
 
 
 
o 
 
o 
 
o 
 
o 
 
o 
 
o 
 
o 
 
o 
 
o 
 
o 
 
 
 
 
 
 
8.3.5.3. 
Study Intervention Interruption or Discontinuation  
 

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Participants with normal or near-normal 
baseline liver enzymes (ALT and/or AST 
and/or ALP <1.5x ULN)
Participants with elevated baseline liver enzymes (ALT 
 
 a with hepatic signs or 
symptomsa or
 
(whichever occurs first) with hepatic signs or symptomsa or
 a for more than 2 weeks 
or 
 
(whichever occurs first) for more than 2 weeks or
 a or 
first) or 
 a 
 or 
or
 
(whichever occurs first) and 
or
 a or 
or 
 a
b or 
b or
 a with hepatic signs or 
symptomsa 
a 
Abbreviations: ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; INR = 
international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal. 
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
b 
 
 
 
 
 
 
 
Resumption of the study intervention after interruption for a hepatic reason can be considered 
only in consultation with the Lilly-designated medical monitor and only if the liver test results 
returned to near baseline and if a self-limited, non-study drug etiology is identified. Otherwise, 
the study intervention should be permanently discontinued. 
8.3.6. 
Major Adverse Cardiovascular Events (MACE)  
Death and nonfatal cardiovascular AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise. This committee will be blinded to treatment 
assignment. 
The nonfatal cardiovascular AEs to be adjudicated include 
 myocardial infarction 
 hospitalization for unstable angina 

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 hospitalization for HF 
 coronary interventions, such as coronary artery bypass graft or percutaneous coronary 
intervention 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack, and 
 urgent HF visits 
8.3.7. 
Safety Topics of Special Interest  
Each occurrence of the below events will be recorded as a separate AE in the CRF. For each 
event assessment of severity, duration (actual date, time of onset, and end times), and 
captured. 
8.3.7.1. 
Vaginal Bleed  
If a participant reports vaginal bleeding while being treated with study intervention, the 
investigator should discontinue study treatment and refer the participant for a gynecological 
assessment. At the discretion of the local physician, this follow-up examination may include a 
Pap smear, endometrial biopsy, or transvaginal ultrasound as the initial test for evaluating the 
endometrium. The gynecological report should be sent to sponsor medical monitor. 
8.3.7.2. 
Breast Screening  
Compliance with routine breast screening is recommended per local guidelines. Abnormal 
finding during breast screening per local guidelines will be recorded as AE. 
8.3.7.3. 
Orthostatic Hypotension  
Symptomatic hypotension-related events (for example, syncope, dizziness, falls, clinically 
significant drop in BP, etc.) 
Orthostatic hypotension: A sustained reduction in systolic blood pressure of at least 20 mmHg 
within 3 minutes of standing after being supine for 5 minutes. 
8.4. 
Pharmacokinetics  
Venous blood samples will be collected from all study participants for measurement of plasma 
concentrations of LY3540378 as specified in the SoA. 
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data, for example, to 
obtain data closer to the time of peak plasma concentrations, to ensure appropriate safety 
monitoring. 
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 LY3540378 sample and dose 
administered must be recorded. 

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Samples will be used to evaluate the PK of LY3540378. Samples collected for analyses of 
LY3540378 plasma concentrations may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
Genetic analyses will not be performed on these plasma samples. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel. 
8.4.1. 
Bioanalysis  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. Concentrations of LY3540378 will be assayed using a validated 
liquid chromatography mass spectrometry method. Analyses of samples collected from 
placebo-treated subjects are not planned. 
Bioanalytical samples collected to measure study intervention concentrations will be retained 
for a maximum of 1 year following the last participant visit for the study. During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism work, protein binding, and/or bioanalytical method cross-validation. 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are described in Section 8.1.2.1. 
8.6. 
Genetics  
A blood sample for DNA isolation may be collected from participants. 
See Section 10.5 for Information regarding genetic research and Section 10.1.12 for details 
about sample retention and custody. 
Additionally, HLA Class II testing may be conducted in order to define the immunophenotypic 
characteristics that might be associated with incidence of injection site reactions observed 
following LY3540378 administration. 
8.7. 
Biomarkers  
samples will be used for exploratory biomarker research, where local 
regulations allow. 
See Clinical Laboratory Tests in Section 10.2, and the SoA for sample collection information. 
Samples will be used for research on the drug target, disease process, variable response to 
LY3540378, pathways associated with HF, mechanisms of action of LY3540378 or research 
methods, or in validating diagnostic tools or assay(s) related to HF. 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  
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be 
collected to determine antibody production against LY3540378. Antibodies may be further 
characterized for their ability to neutralize the activity of LY3540378. To interpret the results of 
immunogenicity, a venous blood sample will be collected at the same time points to determine 
the serum concentrations of LY3540378. All samples for immunogenicity should be taken 
predose when applicable and possible. Upon assay validation, ADAs may be characterized; 
treatment-emergent ADAs are defined in Section 9.3.7. 
If the immunogenicity sample at the last scheduled assessment or discontinuation visit indicates 
TE-ADA, additional samples may be taken until the signal returns to baseline ,that is, no longer 
indicates TE-ADA or for up to 1 year after last dose. 
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3540378 at a laboratory approved by the sponsor. The purpose of retention, the maximum 
duration of retention, and facility for long-term storage of samples is described in Section 
10.1.12. Samples may also be used for development and control of an immunogenicity assay. 
8.9. 
Medical Resource Utilization and Health Economics  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study 

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9. 
Statistical Considerations  
9.1. 
Statistical Hypotheses  
The study hypothesis for the primary objective is that LY3540378 administered SC QW is 
superior to placebo for change from baseline in LARS at Week 26 in participants with 
worsening chronic HFpEF. 
9.1.1. 
Multiplicity Adjustment  
Treatment comparisons will be performed for the primary objective at the full significance level 
of 0.05. No multiplicity adjustments will be made for the analysis of primary, secondary, and 
tertiary objectives. 
9.2. 
Analyses Sets  
This table defines the analysis population and datasets for the purposes of analysis. 
Participant Analysis Set
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 

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described in the CSR. Additional exploratory analyses of the data will be conducted as deemed 
appropriate. 
Baseline is defined as the last non-missing measurement recorded on or before the 
randomization visit, prior to first dose of intervention, unless otherwise specified. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
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 LY3540378 doses to placebo and is 
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 LY3540378 doses with placebo irrespective of adherence to intervention. Thus, safety 
analyses will be conducted using the SS (Section 9.2). 
Exploratory analyses 
atment 
 estimand, which represents the efficacy irrespective of 
adherence to study intervention, may also be used to compare the efficacy of LY3540378 doses 
with placebo for primary and secondary endpoints in the exploratory analyses. The analysis 
g
 policy
SAP. 
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
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 a MMRM with terms: 
 treatment 
 visit 
 treatment-by-visit interaction, and 
 baseline measurement 
Additional covariates such as stratification factors may be added and will be detailed in SAP. 
Logistic regression may be used to examine the treatment difference in binary efficacy 
-square test may be used to examine the treatment 
difference in categorical outcomes.  
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP. 

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9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis  
The primary estimand analysis is described in Section 3. 
The primary efficacy comparison will be based on the contrast between LY3540378 doses of 
25, 50, 100 mg; combination of 50 and 100 mg; and placebo for the absolute change of LARS 
from baseline at screening 
to Week 26. 
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 Endpoints Analysis  
The secondary estimand analysis is described 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 Endpoints Analysis  
The analysis will be detailed in SAP. 
9.3.5. 
Safety Analyses  
Safety assessments will be guided by an estimand comparing safety of LY3540378 doses with 
placebo irrespective of adherence to intervention. Thus, safety analyses will be conducted using 
the SS. 
AEs will be coded from the actual term using the 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, such as orthostatic hypotension (as defined in 
Section 8.3.7.3). 
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 
compare the treatment groups. 
9.3.5.1. 
Central Laboratory Measures, Vital Signs, and Electrocardiograms  
Central laboratory measures, vital signs, and selected ECG parameters will be summarized for 
each scheduled visit by 
 actual measures at baseline and postbaseline 

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 change from baseline to postbaseline, or 
 percent change from baseline to postbaseline. 
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 analyze 
LY3540378 concentration data. 
The relationships between LY3540378 dose and/or concentration and selected efficacy (for 
example, LARS, NT-proBNP, LAEDVI, LAESVI, eGFR, serum creatinine and cystatin-C) and 
safety (for example, BP) endpoints may be characterized, where applicable. Additionally, the 
impact of intrinsic and extrinsic factors, such as age, weight, gender, and renal function on PK 
and/or PD parameters, may be examined as needed. 
If ADA titers are detected from immunogenicity testing, then the impact of immunogenicity 
titers on LY3540378 PK or any relevant efficacy parameters may also be examined. Additional 
analyses may be conducted if they are deemed appropriate. Details on PK and PK/PD analyses 
will be provided in the PK/PD analysis plan. 
9.3.7. 
Immunogenicity Assessments  
If data from validated immunogenicity assays are available, TE-ADAs may be assessed. 
TE-ADAs are defined as 
 a titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs were 
detected at baseline (treatment-induced ADA), or 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 LY3540378 may 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 LY3540378 may also be assessed. Additional details may be provided in the SAP. 
9.3.8. 
Subgroup Analyses  
Subgroup analyses of important factors, such as stratification factor, gender, NYHA class, 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. 
 

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9.4. 
Interim Analysis  
There may be up to 4 interim analyses including primary database lock.   
A planned interim analysis may be conducted when between 40% and 80% of the participants 
complete Week 26 at 
 or discontinue the study. The interim will be for the purpose of 
internal planning and decision-making and may assess safety, PK, and/or efficacy measures. At 
the discretion of the sponsor, the prespecified interim analysis may not be conducted. 
Additional details related to statistical methods will be described in the SAP. If this happens, an 
AC will be formed to review the interim analyses in an unblinded manner. The details regarding 
the number of participants and type of analysis will be provided in the AC charter and in the 
unblinding plan. Information that may unblind the study during the analyses will not be 
reported to study sites or blinded study team members before the study has been unblinded. 
Study sites will receive information about interim results only if deemed necessary for the 
safety of the participants. The study will not be stopped based on the efficacy of LY3540378 
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 EZDB may occur when all 
participants have completed 26 weeks 
 of 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. If there is 
no primary database lock, the primary analysis will be based on the final database lock. 
Early access to the PK and PD data before the interim and primary database locks may be 
conducted to allow population PK/PD analysis and model development. If applicable, this early 
access will be detailed in the Unblinding Plan and the Population PK/PD Analysis Plan. 
9.5. 
Sample Size Determination  
The sample size calculation is based on the primary efficacy estimand and its endpoint, change 
from baseline at Week 26 in LARS. 
For participants who joined study before amendment (b), they were randomized 1:1:1:1 to the 
following intervention groups: 
 LY3540378 25 mg SC QW 
 LY3540378 50 mg SC QW 
 LY3540378 100 mg SC QW, and 
 placebo. 
For participants who joined study after amendment (b), will be randomized 1:2:2:2 to the above 
intervention groups.  
Up to 456 participants will be randomly assigned to ensure at least 114 participants enrolled in 
each of 50 mg, 100 mg, and placebo groups. Assuming a 20% dropout rate, this will result in at 
least 91 completers in each of 50 mg, 100 mg, and placebo group. The number of completers in 
25 mg will be approximately 64 to 91, depending on when the amendment (b) is globally 
implemented. 

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The evaluation of superiority to placebo will be conducted for LY3540378 doses of 50 and 
100 mg and combination of 50 and 100 mg. No adjustment for multiplicity will be performed. 
Assuming a standard deviation of 8.5%, and a 2-sided, alpha level of 0.05, 91 completers for 
each treatment arms will provide 88% power to detect a treatment difference of 4% for the 
primary endpoint for LY3540378 50 mg group versus placebo and LY3540378 100 mg group 
versus placebo, respectively. 

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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences 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, ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations 
 Reporting to the sponsor or designee significant issues related to participant safety, 
participant rights, or data integrity 
 Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement. 
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 

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certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and 
for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
 The investigator or 
 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 Code 
of Federal Regulations 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 to protect the 
personal data. Any participant information, such as 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 
 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. This is done by the site personnel through the informed 
consent process. 
The participant must be informed through the informed consent by the site personnel 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 information security, data integrity, and data 
protection. These processes address management of data transfer, and prevention and 
management of unauthorized access, disclosure, dissemination, alteration or loss of information 
or personal data. These processes include appropriate contingency plan(s) for appropriate and 
timely response in the event of a data security breach. 

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The transfer of personal data is subject to appropriate safeguards through contractual 
relevant legislations including the General Data Protection Regulation (GDPR). 
10.1.5. 
Committees Structure  
External clinical endpoint committee 
An independent clinical endpoint committee, external to Lilly, will be formed to adjudicate 
MACE, all-cause mortality (CV and non-CV death) and HF events (hospitalization and urgent 
visit). This committee will be blinded to treatment assignment. 
10.1.6. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or 
regulation. If the study remains ongoing in some countries and a statistical analysis of an 
incomplete dataset would result in analyses lacking scientific rigor (for example, 
underpowered) or compromise the integrity of the overall analyses (for example, trial not yet 
unblinded), the summary of results will be submitted within 1 year after the end of the study 
globally or as soon as available, whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
Data and documents, including the study protocol, SAP, CSR, and blank or annotated 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  
 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 
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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. 
 Quality tolerance limits will be pre-defined to identify systematic issues that can impact 
participant safety and/or reliability of study results. These pre-defined parameters will 
be monitored during the study and important excursions from the quality tolerance 
limits and remedial actions taken will be summarized in the CSR. 
 Monitoring details describing strategy (for example, risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques are provided in the Monitoring Plan. 
 The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations). 
 Study monitors will perform ongoing source data verification to confirm that data 
transcribed into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the time period outlined in the Clinical Trial 
Agreement unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor. 
 In addition, sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study may be 
audited by sponsor or its representatives, and/or regulatory agencies at any time. 
Investigators will be given notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor. 
An 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. 
Additionally, study intervention administration data will be collected by the participant, via a 
paper source document and will be transcribed by the authorized study personnel into the EDC 
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Additionally, eCOA data (participant-focused outcome instrument) will be directly recorded by 
the participant, into an instrument (for example, handheld smart phone or tablet). The eCOA 
data will serve as the source documentation and the investigator does not maintain a separate 
written or electronic record of these data. 
Data collected via the sponsor-provided data capture system(s) 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 system(s). 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 
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 
 
 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 
designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of the sponsor. Study sites will be closed 
upon study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
 
Discontinuation of further study intervention development 
For site termination: 

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 Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor s procedures, or GCP guidelines 
 Inadequate recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator 
 Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRBs/IECs, 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  
, 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 LY3540378 or after LY3540378 become(s) commercially available. 
 
Sample Type 
Custodian 
Maximum Retention Period After Last 
Participant Visita
Exploratory Biomarkers
Sponsor or Designee
7 years 
Pharmacokinetics
Sponsor or Designee
1 year 
Genetics 
Sponsor or Designee
7 years 
Immunogenicity
Sponsor or Designee
15 years 
a 
Retention periods may differ locally. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table below will be performed 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 central 
laboratory testing (in the table below), the local laboratory must be qualified in accordance with 
applicable local regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 
5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
Laboratory results that could unblind the study will not be reported to investigative sites or 
other blinded. 
 
 

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Clinical Laboratory Tests 
Comments 
Hematology 
Assayed by Lilly-designated laboratory.  
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration 
 
Leukocytes (WBCs)  
  
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 
  
ALP 
  
ALT 
  
AST 
  
GGT 
BUN 
  
Creatinine  
Test will be performed locally for screening purposes and by 
Lilly-designated laboratory for statistical data evaluation. 
For all other visits, results will be generated by Lilly-
designated laboratory.
CK 
Uric acid 
 
Total protein 
  
Albumin 
  
Calcium 
Phosphorus 
Glucose 
  
Lipid Panel 
 

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Clinical Laboratory Tests 
Comments 
HDL-C 
 
Non-HDL-C 
 
LDL-C  
This value will be calculated. If
triglycerides are >400 mg/dL, the direct 
LDL will be assayed.
VLDL-C 
 
Cholesterol 
 
Triglycerides 
 
Urinalysis 
Assayed by Lilly-designated laboratory. 
Specific gravity 
 
pH 
 
Protein 
 
Glucose 
 
Ketones 
 
Bilirubin 
 
Urobilinogen 
 
Blood 
 
Nitrite 
 
Urine leukocyte esterase 
 
Microscopic examination of sediment 
 
Hormones (female) 
FSH 
Assayed by Lilly-designated laboratory. 
Urine Chemistry 
Assayed by Lilly-designated laboratory. 
Albumin 
 
Creatinine 
 
Potassium 
 
Sodium 
 
Calculations 
 
eGFR (CKD-EPI) calculated using creatinine 
Test will be performed locally for screening purposes and by 
Lilly-designated laboratory for statistical data evaluation. 
For all other visits, results will be generated by Lilly-
designated laboratory.
eGFR (CKD-EPI) calculated using cystatin-c 
Generated by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
eGFR (CKD-EPI) calculated using creatinine and 
cystatin-c 
Generated by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
UACR 
Generated by Lilly-designated laboratory. 
Pharmacokinetics Sample - LY3540378 
concentration
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Additional Testing 
 
NT-proBNP 
Test will be performed locally for screening purposes and by 
Lilly-designated laboratory for statistical data evaluation.

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Clinical Laboratory Tests 
Comments 
For all other visits, results will be generated by Lilly-
designated laboratory. Results will not be provided to the 
investigative sites.
BNP  
Test will be performed locally for screening purposes and by 
Lilly-designated laboratory for statistical data evaluation. 
For all other visits, results will be generated by Lilly-
designated laboratory. Results will not be provided to the 
investigative sites.
Cystatin-c 
Assayed by Lilly-designated laboratory. 
hs-cTnT 
Assayed by Lilly-designated laboratory. 
hsCRP 
Assayed by Lilly-designated laboratory. 
HbA1c 
Assayed by Lilly-designated laboratory. 
HLA  Class II 
Assayed by Lilly-designated laboratory 
Results will not be provided to the investigative sites.
 DHEA 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Androstenedione 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
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.
 
  
 
 
 
 
Immunogenicity Samples 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the investigative sites.
Anti-LY3540378 antibodies 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BNP = Brain natriuretic peptide; BUN = blood urea nitrogen; CK = creatine kinase; CKD-EPI = Chronic 
Kidney Disease Epidemiology Collaboration; DHEA = Dehydroepiandrosterone; EDTA = 
Ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate;  GGT = Gamma-glutamyl 
transferase; FSH = Follicle-stimulating hormone; HbA1c = Hemoglobin A1c; HDL-C = High-density 
lipoprotein cholesterol; HLA = Human leukocyte antigen; hsCRP  = C-reactive protein, high- sensitivity; hs-
cTnT = Troponin. high sensitivity; LDL-C = Low-density lipoprotein cholesterol; NT-proBNP = N-terminal 
pro BNP; RBC = red blood cells; UACR = Urinary albumin/creatinine ratio; VLDL-C = Very-low-density 
lipoprotein cholesterol; WBC = white blood cells. 
 
 
 

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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 min to 4 hr after 
the start of the event. 
 Note: The optimal collection 
time is 1 to 2 hr after the start 
of event.
Serum
total tryptase
Serum
complements (C3, C3a, and C5a)
Serum 
cytokine panel (IL-
panel that includes these 3 cytokines)  
Collect only if not already 
collected on the same day as the 
event. 
 Note: If collecting, collected up 
to 12 hr after the start of the 
event.
Serum
LY3540378 ADA
Plasma 
LY3540378 concentration 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
a 
All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this 
will not be considered a protocol deviation. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
 
 

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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae.  
 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE.

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 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 1 or 
more of the criteria listed: 
Results in death 
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. 
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 physicia
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. 
Results in persistent disability or incapacity 
 The term disability means a substan
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. 
Is a congenital anomaly or birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
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 

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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. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and PC 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 
medical records, in accordance with 
practice. AE/SAE 
information is reported on the appropriate CRF page and PC information is reported on 
the PC 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 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and the 
PC 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 

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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 or 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 a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
one of the pre-defined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A reasonable possibility  of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB in their assessment. 
 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 a SAE follow-up report with the updated causality assessment.

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 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 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) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a SAE paper form (see next section) or to 
the sponsor by telephone. 
 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 a SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

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 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 evaluate the reported SAEs, including confirmation of 
relatedness and assessment of expectedness. The sponsor has processes for safety reports 
for identification, recording, and expedited reporting of suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements. The sponsor will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
 An investigator who receives an investigator safety report describing a 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. 
Women not of childbearing potential 
Females are considered WNOCBP if they 
 have a congenital anomaly such as Müllerian agenesis 
 are infertile due to surgical sterilization, or 
 are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-oophorectomy, 
bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal state 
The postmenopausal state is defined as a woman: 
 at any age at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note; or 
 aged at least 40 years and up to 55 years with an intact uterus, not on hormone therapya, 
who has had cessation of menses for at least 12 consecutive months without an 
alternative medical cause, AND with a follicle-stimulating hormone >40 mIU/mL; or 
 55 years or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or 
a Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor 
modulators, or chemotherapy that could induce transient amenorrhea. 
 
 

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10.4.2. 
Contraception Guidance  
The table below describes contraception guidance for men. 
Topic 
Guidance 
For all men  
should refrain from sperm donation for the 
duration of the study and for 135 days.  
Contraception for men with partners of 
childbearing potential  
 either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 must use condoms during intercourse for the 
duration of the study, and 
 for 135 days after end of study. 
Contraception for men in exclusively 
same sex relationships, as their 
preferred and usual lifestyle 
Are not required to use contraception 
Methods of contraception for male participants and their female partners 
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 
barrier method with use of a spermicide 
 male condom with spermicide 
 diaphragm with spermicide or cervical sponge, or 
 female condom with spermicide 
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 
 
 

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10.5. 
Appendix 5: Genetics  
Use/Analysis of DNA 
 Genetic 
susceptibility to, and severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where local 
regulations and IRB/IEC allow, an optional blood sample will be collected for DNA 
analysis from consenting participants. 
 DNA samples will be used for research related to HF and related diseases. They may 
also be used to develop tests or assays including diagnostic tests related to LY3540378 
and HFpEF. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the entire 
genome (as appropriate). 
 The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to LY3540378 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 LY3540378 continues but no longer than as 
indicated in Section 10.1.12. 
 
 

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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
10.6.1. 
Hepatic Evaluation Testing  
See Section 8.3.5 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
The local laboratory must be qualified in accordance with applicable local regulations. If testing 
is not available in certain regions based on local requirements, consult with Lilly-designated 
medical monitor. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing:
  Hemoglobin 
   HAV total antibody
a
  Hematocrit 
   HAV IgM antibody
  Erythrocytes (RBCs - red blood cells)
Hepatis B virus (HBV) testing: 
  Leukocytes (WBCs - white blood cells)
   Hepatitis B surface antigen (HBsAg)
  Differential:
   Hepatitis B surface antibody (anti-HBs)
      Neutrophils 
   Hepatitis B core total antibody (anti-HBc)
      Lymphocytes
   Hepatitis B core IgM antibody
      Monocytes
   HBV DNAb
      Basophils
Hepatis C virus (HCV) testing:
      Eosinophils 
   HCV total antibodya
  Platelets
   HCV RNAb
  Cell morphology (RBC and WBC)
Hepatitis D virus (HDV) testingc:
Hepatic Clinical Chemistry Panel
   HDV total antibodya
  Total bilirubin
   HDV IgM antibody
  Direct bilirubin 
   HDV RNAb
  Alkaline phosphatase (ALP)
Hepatitis E virus (HEV) testing:
  Alanine aminotransferase (ALT)
   HEV IgG antibody
  Aspartate aminotransferase (AST)
   HEV IgM antibody
  Gamma-glutamyl transferase (GGT)
   HEV RNAb
  Creatine kinase (CK)
Anti-nuclear antibody (ANA)
Hepatic Coagulation Panel
Anti-smooth muscle antibody (ASMA) or anti-
actin antibody
  Prothrombin time, INR (PT-INR)
Immunoglobulin IgA (quantitative)
Urine Chemistry
Immunoglobulin IgG (quantitative)
  Drug screen
Immunoglobulin IgM (quantitative)
Haptoglobin
 
Tests assayed by investigator-designated local laboratory  

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Acetaminophen
Cytomegalovirus (CMV) testing:
Acetaminophen protein adductsd 
   CMV antibody 
Alkaline phosphatase isoenzymes 
   CMV DNAb
Ceruloplasmin
Herpes simplex virus (HSV) testing:
Copper
   HSV (Type 1 and 2) antibody
Ethyl alcohol (EtOH) 
   HSV (Type 1 and 2) DNAb
Phosphatidylethanol (PEth) 
Liver kidney microsomal type 1 (LKM-1) antibody
Urine Chemistry
Microbiology 
   Ethyl glucuronide (EtG)
Culture: 
Epstein-Barr virus (EBV) testing: 
   Blood
   EBV antibody 
   Urine 
   EBV DNAb
     
a 
If lab does not offer total antibody testing, IgG and IgM are acceptable substitute. 
b 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c 
If HDV testing is not available, HBV testing may be sufficient. If HBV testing is positive, consult with the Lilly-designated 
medical monitor. 
d      Availability of acetaminophen protein adducts testing is limited, so testing may be performed at central labs, if needed. 

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Appendix 7: Provisions for Changes in Study Conduct During Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the 
study. Examples include pandemics or natural disasters. These disruptions may limit the ability 
of the investigators, participants, or both to attend on-site visits or to conduct planned study 
procedures. 
Implementing changes under exceptional circumstances 
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 
 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 

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Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but are 
not limited to, 
 AE review, concomitant medications, etc. 
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, administration of PROs if validated for these types of visits, 
administration of study intervention, and collection of health information. 
Other alternative locations: A local laboratory may be used for laboratory draws. 
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 central laboratory testing. However, 
central laboratory testing must be retained for NTpro-BNP. The local laboratory must be 
qualified in accordance with applicable local regulations. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions 
may include: 
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit, 
 
 
 arranging delivery of study supplies, and 
 working with the sponsor to determine how study intervention that is typically 
administered on site will be administered to the participant; for example, during a 
mobile healthcare visit or at an alternate location such as an infusion center. 

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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 par
 
 When delivering supplies to a location other than the study site (for example, 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition 
of any unused or completed study supplies. 
If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, this additional requirement must be met: 
 Only authorized study personnel may supply, prepare, or administer study 
intervention. 
Adjustments to visit windows 
Whenever 
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. 
 
This table describes the allowed adjustments to visit windows. 
Visit Number
Tolerance
Visits 3 through 
24
Visits 801 and 
802 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity 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 or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 

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Source documents generated at a location other than the study site should be part of the 
 source documentation and should be transferred to the site in a secure and timely 
manner. 
The below figure provides an overview of screening and randomization.  
 

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10.7. 
Appendix 8: Abbreviations and Definitions  
Term 
Definition 
Abuse 
Use of a study intervention for recreational purposes or to maintain an 
addiction or dependence 
ADA 
anti-drug antibody 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in 
accordance with Directive 2001/83/EC, irrespective of changes to the labelling 
of the medicinal product, which is used as an investigational medicinal 
product 
authorized AxMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State concerned in 
accordance with Directive 2001/83/EC, irrespective of changes to the labelling 
of the medicinal product, which is used as an auxiliary medicinal product 
AxMP 
auxiliary medicinal product. See also NIMP. 
A medicinal product used for the needs of a clinical trial as described in the 
protocol, but not as an investigational medicinal product. Examples include 
rescue medication, challenge agents, agents to assess endpoints in the clinical 
trial, or background treatment. AxMP does not include investigational 
medicinal product (IMP) or concomitant medications. Concomitant 
medications are medications unrelated to the clinical trial and not relevant for 
the design of the clinical trial 
blinding 
A single-blind study is one in which the investigator and/or 
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 
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 participants are aware of the treatment received. 
BNP 
brain natriuretic peptide  
BP 
blood pressure 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Companion 
diagnostic  
An in vitro diagnostic device (assay or test) that provides information that is 
essential for the safe and effective use of a corresponding therapeutic product 
complaint 
A complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, purity, durability, reliability, safety 
or effectiveness, or performance of a drug or drug delivery system. 

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compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable 
regulatory requirements. 
COPD 
chronic obstructive pulmonary disease  
CSR 
clinical study report 
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. 
CT 
computed tomography 
CV 
cardiovascular 
DHEA 
dehydroepiandrosterone 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ECHO 
echocardiogram 
eCOA 
electronic clinical outcome assessment 
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. 
GCP 
Good Clinical Practice 
GDPR 
EU-General Data Protection Regulation 
HF 
heart failure 
HFpEF 
heart failure with preserved ejection fraction 
HLA class II 
human leukocyte antigen class II 
IB 
 
AC 
Assessment Committee  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
 
A medicinal product which is being tested or used as a reference, including as 
a placebo, in a clinical trial 
Index event 
A recent hospitalization for HF requiring at least 2 doses of intravenous 
diuretics or an out- of- hospital encounter (for example, Emergency Room, 
clinic visit, infusion clinic, etc.) for HF requiring at least 2 doses of 
intravenous diuretics. 

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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 
consent is documented by means of a written, signed, and dated informed 
consent form. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used 
as a reference in a clinical trial, including products already on the market when 
used or assembled (formulated or packaged) in a way different from the 
authorized form, or marketed products used for an unauthorized indication, or 
marketed products used to gain further information about the authorized form. 
ISR 
Injection site reaction 
IV 
Intravenous 
IWRS 
interactive web-response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
left atrium 
LAEDVI 
left atrial end-diastolic volume index 
LAESVI 
left atrial end-systolic volume index 
LARS 
left atrial reservoir strain 
LV 
left ventricle 
LVAD 
left ventricular assist device 
LVEDV 
left ventricular end-diastolic volume  
LVESV 
left ventricular end-systolic volume 
LVEF 
left ventricular ejection fraction 
LVGLS 
left ventricular global longitudinal strain 
MAD 
multiple-ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 

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Medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant 
or the error leads to an AE. Medication error generally involve a failure to 
participant, the right drug, the right dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication 
errors:  
 
 
-use date 
perly stored medication 
with the medication's labeling (for example, Summary of Product 
Characteristics, IB, local label, protocol), or 
 or both. 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with 
the prescribed dosing regimen, indication, or both, or is obtained without a 
prescription 
MMRM 
mixed model for repeated measures  
MRI 
magnetic resonance imaging 
NIMP 
non-investigational medicinal product See AxMP 
A medicinal product used for the needs of a clinical trial as described in the 
protocol, but not as an investigational medicinal product. Examples include 
rescue medication, challenge agents, agents to assess endpoints in the clinical 
trial, or background treatment. 
 
NT-proBNP 
N-terminal pro-B-type natriuretic peptide 
NYHA 
New York Heart Association 
participant 
Equivalent to CDISC term 
clinical trial, either as recipient of an investigational medicinal product or as a 
control 
PC 
product complaint 
PCWP 
pulmonary capillary wedge pressure 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Status 
PK/PD 
pharmacokinetics/pharmacodynamics 
PPS 
per-protocol set: The set of data generated by the subset of participant who 
sufficiently complied with the protocol to ensure that these data would be 
likely to exhibit the effects of treatment, according to the underlying scientific 
model. 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 

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PT-INR 
prothrombin time  international normalized ratio 
QTc 
corrected QT interval 
QW 
once a week 
RXFP1 
relaxin family peptide receptor 1 
RXFP2 
relaxin family peptide receptor 2 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
screen 
The act of determining if an individual meets minimum requirements to 
become part of a pool of potential candidates for participation in a clinical 
study.  
SGLT-2i 
sodium-glucose cotransporter-2 inhibitor 
SOA 
schedule of activities 
SS 
safety analysis set 
SUSAR 
Suspected unexpected serious adverse reactions 
Refers to an adverse event that occurs in a clinical trial participant, which is 
assessed by the sponsor and or study investigator as being unexpected, serious 
and as having a reasonable possibility of a causal relationship with the study 
intervention. 
TBL 
total bilirubin 
TD 
temporary discontinuation 
TE-ADA 
Treatment emergent antidrug antibodies 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that 
emerges during a defined treatment period, having been absent pretreatment, 
or worsens relative to the pretreatment state, and does not necessarily have to 
have a causal relationship with this treatment. 
ULN 
upper limit of normal 
WHF 
worsening heart failure 
WOCBP 
women of childbearing potential 
 
 

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10.9. 
Appendix 9: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]: (01-Jun-2023) 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because it is likely to have a significant impact 
on the safety or the rights of the study participants. 
Overall Rationale for the Amendment: 
The overall rationale of this amendment is to modify the inclusion and exclusion criteria and 
schedule of activities. 
 
Section # and Name
Description of Change
Brief Rationale
Title page 
Included both EudraCT number and EU 
CT number 
To bring the protocol under EU 
CT Regulation  
1.1 Synopsis 
Updated the section to align with the 
changes in the main body of the protocol 
and as per latest protocol template 
For consistency 
1.3. Schedule of Activities 
(SoA) 
Visits 1 through 16 
 
Updated the screening period to Visit 1 
only. Initially the screening period was 
extended to Visit 3. 
Correction 
-
 
For clarification 
Removed the Visit interval tolerance 
(days) for Visit 1 
 
Changed 
 to telehealth 
visits  
 
Deleted the measurement of Weight, 
Vital signs, Physical examination, 
Register visit with IWRS, Dispense study 
intervention via IWRS, Administer study 
intervention on site, Train participants 
and/or caregiver in study intervention 
administration, at 
 
For clarification 
Deleted the measurement of Patient-
Reported Outcomes 
 
PGIS-HF Overall Health, 
PGIC-HF Overall Health, PGIS-HF 
Symptom Severity, and PGIC-HF 
Symptom Severity at 
 
For clarification 
 
Correction 

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Section # and Name
Description of Change
Brief Rationale
Correction 
and added to 
For clarification  
 and added at Visit 
  
For clarification  
section 
For clarification 
1.3. Schedule of Activities 
(SoA) 
, ED, 
and Follow-Up
-
 
Correction 
Includes 
BP (supine and standing), pulse rate, 
comments section 
Correction 
-
ECG at UV if medically indicated at PI 
 
For clarification 
3. Objectives, Endpoints, 
and Estimands 
-
-
proBNP endpoint 
For clarification. Using 
log(NTproBNP) instead of 
NTproBNP alone will reduce the 
variability 
safety objective 
Correction 
tertiary endpoint 
For clarification 
Change from 
baseline to the average of 
 and 
Week 26 in log-transformed NT-
 
Using log(NTproBNP) instead of 
NTproBNP alone will reduce the 
variability which may better 
detect the treatment effect 
4.1. Overall Design 
 
 
5.1. Inclusion Criteria 
Modified the inclusion criterion 2 
For clarification
Modified the inclusion criterion 3 
For clarification
Modified the inclusion criterion 4 
To expand the access to eligible 
participants
Modified the inclusion criterion 6 
To expand the access to eligible 
participants 
 
To expand the access to eligible 
participants 
In inclusion criterion 8, changed the 
lower cut-
-off of 
 ml/min/1.73 m  
To expand the access to eligible 
participants 
Modified the inclusion criterion 9 
For clarification 
5.2. Exclusion Criteria 
Deleted exclusion criterion 17 
For clarification 

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Section # and Name
Description of Change
Brief Rationale
and 
PVA (pulmonary vein isolation 
ablation)  
For clarification 
In exclusion criterion 19, added 
 
Correction 
Modified the exclusion criterion 20 
For clarification 
Modified the exclusion criterion 21 
For clarification 
Modified the exclusion criterion 22 
To expand the access to eligible 
participants 
 
For clarification 
Modified the exclusion criterion 24 
For clarification 
Modified the exclusion criterion 26 
For clarification 
Modified the exclusion criterion 27 
For clarification 
Modified the exclusion criterion 29 
For clarification 
In exclusion criterion 32, removed 
 
For clarification 
33 
For clarification 
Modified the exclusion criterion 38 
For clarification 
In exclusion criterion 40, added 
 
For clarification 
5.3. Lifestyle 
Considerations 
 
For consistency 
6. Study Interventions and 
Concomitant Therapy 
Updated the language 
Updated as per latest protocol 
template 
6.5. Dose Modification 
the language 
 
Added 
or lower back from 100 to 50 mg as 
 
For clarification 
7.1.4. Temporary 
Discontinuation 
 
For clarification 
8.1.2. Other Efficacy 
Assessments 
-
-
proBNP 
For clarification 
8.2.1. Physical 
Examinations 
 
For clarification 
8.3.1. Timing and 
Mechanism for Collecting 
Events 
Pregnancy in female participants and 
 
To update as per contraceptive 
guidance 
Changed the mechanism for reporting 
To update the mechanism of 
reporting 

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Section # and Name
Description of Change
Brief Rationale
Pregnancy in 
female participants and female partners 
 
8.3.6. Major Adverse 
Cardiovascular Events 
(MACE) 
nonfatal cardiovascular AEs to be 
adjudicated 
Correction 
8.3.7.2. Breast screening 
screening per local guidelines will be 
 
For clarification 
8.4. Pharmacokinetics 
 
For clarification 
8.6. Genetics 
the language to allow for collection of 
genetic sampling to be optional 
Correction 
9.1. Statistical Hypotheses 
Modified the language in the first 
paragraph 
For clarification 
9.3.1. General 
Considerations 
Removed paragraph 3 
For clarification 
Removed continuous data and categorical 
data paragraphs 
Correction 
(defined as evidence of atrial fibrillation 
or atrial flutter on the screening ECG) 
 
For clarification 
Modified the language regarding the 
additional covariates and regression 
models 
For clarification 
9.3.4. Tertiary Endpoints 
Analysis 
Removed the text 
For clarification 
9.3.5.1. Central Laboratory 
Measures, Vital Signs, and 
Electrocardiograms 
Removed paragraphs 2 and 3 
Correction 
9.4. Interim Analysis 
Modified the language to include up to 4 
interim analyses 
For re-evaluation of sample size 
OR to trigger activities for future 
development 
Added language to clarify early access to 
PK and PD data 
For clarification 
10.1.4. Data Protection 
Updated the language 
Updated as per latest protocol 
template 
10.1.5. Committees 
Structure 
paragraph 
For clarification 
10.3.6. Regulatory 
Reporting Requirements 
Updated the language 
Updated as per latest protocol 
template 
10.5. Appendix 5: Genetics 
 
Correction 
Throughout the protocol 
Minor formatting and editorial changes 
Minor, therefore, not detailed 
 

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